Morpholine derivatives and their use as therapeutic agents

ABSTRACT

The present invention relates to compounds of formula (I) ##STR1## wherein X is --NR 6  R 7  or C-- or N-linked imidazolyl; Y is hydrogen or C 1-4  alkyl optionally substituted by hydroxy; R 1 , R 2 , R 3 , R 4  and R 5  are selected from a variety of suitable aromatic substituents; R 6  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4  alkyl, phenyl, or C 2-4  alkyl substituted by C 1-4  alkoxy or hydroxy; R 7  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl C 1-4  alkyl, phenyl, or C 2-4  alkyl substituted by one or two of C 1-4  alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or NR 6  R 7  is a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, optionally containing one of O, S, NR 8 , S(O) or S(O) 2  and optionally substituted by one or two of hydroxy 1-4  alkyl, C 1-4  alkoxy C 1-4  alkyl, oxo, COR a  or CO 2  R a  ; or NR 6  R 7  forms a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; and R 9a  and R 9b  are each independently hydrogen or C 1-4  alkyl, or R 9a  and R 9b  are joined so, together with the carbon atoms to which they are attached, there is formed a C 5-7  ring; or a pharmaceutically acceptable salt thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia.

This application is a 371 PCT/GB95/01868 filed Aug. 7, 1995.

This invention relates to a class of morpholine derivatives which areuseful as tachykinin antagonists.

The tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in peripheral nervous and circulatory systems.

At present, there are three known mammalian tachykinins referred to assubstance P, neurokinin A (NKA, substance K, neuromedin L) andneurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides(1985) 6(suppl. 3), 237-242). The current nomenclature designates thethree tachykinin receptors mediating the biological actions of substanceP, NKA and NKB as the NK₁, NK₂ and NK₃ receptors, respectively.

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardiovascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitis, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease, ocularinjury and ocular inflammatory diseases, proliferativevitreoretinopathy, irritable bowel syndrome and disorders of bladderfunction including cystitis and bladder detruser hyper-reflexia isreviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists",C. A. Maggi, R Patacchini, P. Rovero and A. Giachetti, J. Auton.Pharmacol. (1993) 13, 23-93.

For instance, substance P is believed inter alia to be involved in theneurotransmission of pain sensations Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (1987) 8, 506-510!, specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25, 1009) and in arthritis Levine et al in Science (1984) 226,547-549!. Tachykinins have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as inflammatory boweldisease Mantyh et al in Neuroscience (1988) 25(3), 817-37 and D. Regoliin "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)! and emesis F. D. Tattersall etal, Eur. J. Pharmacol., (1993) 250, R5-R6!. It is also hypothesised thatthere is a neurogenic mechanism for arthritis in which substance P mayplay a role Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al,"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10!. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis, and fibrositisO'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8!. Otherdisease areas where tachykinin antagonists are believed to be useful areallergic conditions Hamelet et al, Can. J. Pharmacol. Physiol. (1988)66, 1361-7!, immunoregulation Lotz et al, Science (1988) 241, 1218-21and Kimball et al, J. Immunol. (1988) 141(10), 3564-9! vasodilation,bronchospasm, reflex or neuronal control of the viscera Mantyh et al,Proc. Natl. Acad. Sci., USA (1988) 85, 3235-9! and, possibly byarresting or slowing β-amyloid-mediated neurodegenerative changesYankner et al, Science (1990) 250, 279-82! in senile dementia of theAlzheimer type, Alzheimer's disease and Down's Syndrome.

Tachykinin antagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) Langdon et al,Cancer Research (1992) 52, 4554-7!.

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral sclerosis J. Luber-Narod etal, poster C.I.N.P. XVIIIth Congress, 28th Jun. 2nd Jul. 1992!, and indisorders of bladder function such as bladder detrusor hyper-reflexia(The Lancet, 16th May 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosus (Europeanpatent specification no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis (European patent specification no. 0 394989).

European patent specification no. 0 577 394 (published 5th Jan. 1994)discloses morpholine and thiomorpholine tachykinin receptor antagonistsof the general formula ##STR2## wherein R¹ is a large variety ofsubstituents; R² and R³ are inter alia hydrogen;

R⁴ is inter alia ##STR3## R⁵ is inter alia optionally substitutedphenyl; R⁶, R⁷ and R⁸ are a variety of substituents;

X is O, S, SO or SO₂ ;

Y is inter alia O; and

Z is hydrogen or C₁₋₄ alkyl.

We have now found a further class of non-peptides which are potentantagonists of tachykinins, especially of substance P.

It is desirable that compounds may be administered orally and byinjection. Certain compounds have now been discovered which act aspotent non-peptide tachykinin antagonists and which, by virtue of theiradvantageous aqueous solubility, are particularly easily formulated foradministration by both the oral and injection routes, for example inaqueous media.

The present invention provides compounds of the formula (I): ##STR4##wherein X is a group of the formula NR⁶ R⁷ or a C-- or N-linkedimidazolyl ring;

Y is hydrogen or C₁₋₄ alkyl optionally substituted by a hydroxy group;

R¹ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CN, SR^(a),SOR^(a), SO₂ R^(a), CO₂ R, CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆ alkynyl orC₁₋₄ alkyl substituted by C₁₋₄ alkoxy, wherein R^(a) and R^(b) eachindependently represent hydrogen or C₁₋₄ alkyl;

R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄alkoxy or CF₃ ;

R³ is hydrogen, halogen or CF₃ ;

R⁴ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, CF₃, NO₂, CN,SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl,C₂₋₆ -alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, wherein R^(a)and R^(b) are as previously defined;

R⁵ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄alkoxy or CF₃ ;

R⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl,phenyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy or hydroxy;

R⁷ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl,phenyl, or C₂₋₄ alkyl substituted by one or two substituents selectedfrom C₁₋₄ alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ringcontaining one or two heteroatoms selected from N, O and S;

or R⁶ and R⁷, together with the nitrogen atom to which they areattached, form a saturated or partially saturated heterocyclic ring of 4to 7 ring atoms, which ring may optionally contain in the ring oneoxygen or sulphur atom or a group selected from NR⁸, S(O) or S(O)₂ andwhich ring may be optionally substituted by one or two groups selectedfrom hydroxyC₁₋₄ alkyl, C₁₋₄ alkoxyC₁₋₄ alkyl, oxo, COR^(a) or CO₂ R^(a)where R^(a) is as previously defined;

or R⁶ and R⁷ together with the nitrogen atom to which they are attached,form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;

R⁸ is hydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl or C₁₋₄ alkoxyC₁₋₄ alkyl;and

R^(9a) and R^(9b) are each independently hydrogen or C₁₋₄ alkyl, orR^(9a) and R^(9b) are joined so, together with the carbon atoms to whichthey are attached, there is formed a C₅₋₇ ring; and pharmaceuticallyacceptable salts thereof.

A preferred class of compounds of formula (I) is that wherein R¹ ishydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃.

Another preferred class of compounds of formula (I) is that wherein R²is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃.

Also preferred is the class of compounds of formula (I) wherein R³ ishydrogen, fluorine, chlorine or CF₃.

A particularly preferred class of compounds of formula (I) is thatwherein R¹ is fluorine, chlorine or CF₃.

Another particularly preferred class of compounds of formula (I) is thatwherein R² is hydrogen, fluorine, chlorine or CF₃.

Also particularly preferred is the class of compounds of formula (I)wherein R³ is hydrogen, fluorine, chlorine or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro or 3-CF₃.

More preferably R² is 5-fluoro or 5-CF₃.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ is hydrogen.

A further preferred class of compound of formula (I) is that wherein R⁴is hydrogen.

Another preferred class of compounds of formula (I) is that wherein R⁵is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen and R⁵ is hydrogen or 4-fluoro.

Yet another preferred class of compounds of formula (I) is that whereinR⁶ represents hydrogen, C₁₋₆ alkyl or C₂₋₄ alkyl substituted by C₁₋₆alkoxy.

A yet further preferred class of compounds of formula (I) is thatwherein R⁷ represents hydrogen, C₁₋₆ alkyl or C₂₋₄ alkyl substituted byC₁₋₆ alkoxy.

Also preferred is the class of compounds of formula (I) wherein R⁶ andR⁷, together with the nitrogen atom to which they are attached, form asaturated heterocyclic ring of 4, 5 or 6 ring atoms which may optionallycontain in the ring one oxygen atom or the group NR⁸ (where R⁸ ishydrogen or methyl) and which ring may be optionally substituted byhydroxyC₁₋₄ alkyl, C₁₋₄ alkoxyC₁₋₄ alkyl, oxo, COR^(a) or CO₂ R^(a).

In particular, the group NR⁶ R⁷ preferably represents NH₂, NHCH₃,N(CH₃)₂, azetidinyl, morpholino, thiomorpholino, piperazino, piperidinoor pyrrolidino.

Also preferred is the class of compounds of formula (I) wherein R^(9a)and R^(9b) are each independently hydrogen or methyl. Preferably R^(9a)is hydrogen. Preferably R^(9b) is hydrogen. Most preferably R^(9a) andR^(9b) are both hydrogen.

From the foregoing it will be appreciated that a particularly aptsub-group of compounds of this invention are those of the formula (Ia)and pharmaceutically acceptable salts thereof: ##STR5## wherein A¹ isfluorine or CF₃ ;

A² is fluorine or CF₃ ;

A³ is fluorine or hydrogen; and X and Y are as defined in relation toformula (I).

A preferred group X for compounds of formula (I) or (Ia) is the NR⁶ R⁷group where R⁶ and R⁷ each independently represent hydrogen, C₁₋₆ alkylor C₂₋₄ alkyl substituted by C₁₋₆ alkoxy, or R⁶ and R⁷, together withthe nitrogen atom to which they are attached, form a saturatedheterocyclic ring of 4, 5 or 6 atoms which may optionally contain in thering one oxygen atom or the group NR⁸, where R⁸ is hydrogen or methyl.

A preferred group Y for compounds of the formulae (I) or (Ia) is themethyl or CH₂ OH group.

Where the group NR⁶ R⁷ forms a saturated heterocylic ring of 4 to 7 ringatoms which may optionally contain in the ring one oxygen or sulphuratom or a group selected from NR⁸, S(O) or S(O)₂, suitable heterocylicgroups include azetidinyl, pyrrolidino, piperidino, homopiperidino,piperazino, N-methylpiperazino, morpholino and thiomorpholino.

Suitable substituents on the saturated heterocyclic ring include CH₂ OH,CH₂ OCH₃, oxo, CHO, CO₂ H, CO₂ CH₃, and CO₂ CH₂ CH₃.

When used herein the term "halogen" means fluorine, chlorine, bromineand iodine. The most apt halogen are fluorine and chlorine of whichfluorine is preferred.

When used herein the term "alkyl" or "alkoxy" as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

The term "alkenyl" as a group or part of a group means that the group isstraight or branched and contains at least one double bond. Examples ofsuitable alkenyl groups include vinyl and allyl.

The term "alkynyl" as a group or part of a group means that the group isstraight or branched and contains at least one triple bond. An exampleof a suitable alkynyl group is propargyl.

Suitable cycloalkyl and cycloalkyl-alkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl andcyclobutylmethyl.

Where the group NR⁶ R⁷ represents a heteroaliphatic ring of 4 to 7 ringatoms and said ring is partially saturated, a particularly preferredgroup is 3-pyrroline.

Where the group NR⁶ R⁷ represents a non-aromatic azabicyclic ringsystem, such a system may contain between 6 and 12, and preferablybetween 7 and 10, ring atoms. Suitable rings include 5-azabicyclo2.1.1!hexyl, 5-azabicyclo 2.2.1!heptyl, 6-azabicyclo 3.2.1!octyl,2-azabicyclo 2.2.2!octyl, 6-azabicyclo 3.2.2!nonyl, 6-azabicyclo3.3.1!nonyl, 6-azabicyclo 3.2.2!decyl, 7-azabicyclo 4.3.1!decyl,7-azabicyclo 4.4.1!undecyl and 8-azabicyclo 5.4.1!dodecyl, especially5-azabicyclo 2.2.1!heptyl and 6-azabicyclo 3.2.1!octyl.

Where R⁷ represents a C₂₋₄ alkyl group substituted by a 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S, suitable rings include pyrrolidino, piperidino, piperazino,morpholino, or thiomorpholino. Particularly preferred are nitrogencontaining heteroaliphatic rings, especially pyrrolidino and morpholinorings.

Specific compounds within the scope of the present invention include:

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaninobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-imidazolylbut-2-yn-yl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine;

4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine;

3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;

3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)-2-(R)-(1-(R)1-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;

4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;`and pharmaceutically acceptable salts thereof.

Further preferred compounds within the scope of the present inventioninclude:

4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine;

4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;

2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;

-4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine;

4-(4-(7-azabicyclo2.2.1!heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine;and pharmaceutically acceptable salts thereof.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts such as those formed with hydrochloric acid,fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid,acetic acid, citric acid, tartaric acid, carbonic acid or phosphoricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The pharmaceutically acceptable salts of the present invention may beformed by conventional means, such as by reacting the free base form ofthe product with one or more equivalents of the appropriate acid in asolvent or medium in which the salt is insoluble, or in a solvent suchas water which is removed in vacuo or by freeze drying or by exchangingthe anions of an existing salt for another anion on a suitable ionexchange resin.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the "parent drug" or "parent molecule")that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The preferred compounds of the formula (I), and (Ia) will have the 2-and 3- substituent cis and the preferred stereochemistry at the2-position is that possessed by the compound of Example 1 (i.e. 2-(R)-),the preferred stereochemistry of the 3-position is that possessed by thecompound of Example 1 (i.e. 3-(S)), and the preferred stereochemistry ofthe carbon to which the group Y is attached is either (R) when Y is C₁₋₄alkyl (e.g. methyl) or (S) when Y is C₁₋₄ alkyl substituted by hydroxy(e.g. CH₂ OH). Thus for example as shown in formula (Ib) ##STR6##

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include thosecomprising a compound of formula (I), as the active ingredient, inassociation with a surface-active agent (or wetting agent or surfactant)or in the form of an emulsion (as a water-in-oil or oil-in-wateremulsion).

Suitable surface-active agents include, in particular, non-ionic agents,such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) andother sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with asurface-active agent will conveniently comprise between 0.05 and 5%surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g. egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example gylcerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion will preferably comprisefat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, andhave a pH in the range of 5.0 to 8.0.

Particularly preferred emulsion compositions are those prepared bymixing a compound of formula (I) with Intralipid™ or the componentsthereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention futher provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous system such as anxiety,depression, psychosis and schizophrenia; epilepsy; neurodegenerativedisorders such as dementia, including AIDS related dementia, seniledementia of the Alzheimer type, Alzheimer's disease and Down's syndrome;demyelinating diseases such as multiple sclerosis (MS) and amyotrophiclateral sclerosis (ALS; Lou Gehrig's disease) and otherneuropathological disorders such as peripheral neuropathy, for exampleAIDS related neuropathy, diabetic and chernotherapy-induced neuropathy,and postherpetic and other neuralgias; neuronal damage, such ascerebralischemic damage and cerebral edema in cerebrovascular disorders;small cell carcinomas such as small cell lung cancer; respiratorydiseases, particularly those associated with excess mucus secretion suchas chronic obstructive airways disease, bronchopneumonia, chronicbronchitis, asthma, and bronchospasm; airways diseases modulated byneurogenic inflammation; diseases characterised by neurogenic mucussecretion, such as cystic fibrosis; diseases associated with decreasedglandular secretions, including lacrimation, such as Sjogren's syndrome,hyperlipoproteinemias IV and V, hemocromatosis, sarcoidosis, andamyloidosis; inflammatory diseases such as inflammatory bowel disease,psoriasis, fibrositis, ocular inflammation, osteoarthritis, rheumatoidarthritis, pruritis and sunburn; allergies such as eczema and rhinitis;hypersensitivity disorders such as poison ivy; ophthalmic diseases suchas conjunctivitis, vernal conjunctivitis, dry eye syndrome, and thelike; ophthalmic conditions associated with cell proliferation such asproliferative vitreoretinopathy; cutaneous diseases such as contactdermatitis, atopic dermatitis, urticaria, and other eczematoiddermatitis; addiction disorders including the withdrawal responseproduced by chronic treatment with, or abuse of, drugs such asbenzodiazepines, opiates, cocaine, alcohol and nicotine; stress relatedsomatic disorders; reflex sympathetic dystrophy such as shoulder/handsyndrome; dysthymic disorders; adverse immunological reactions such asrejection of transplanted tissues and disorders related to immuneenhancement or suppression such as systemic lupus erythematosus;gastrointestinal (GI) disorders, including inflammatory disorders anddiseases of the GI tract such as gastritis, gastroduodenal ulcers,gastric carcinomas, gastric lymphomas, disorders associated with theneuronal control of viscera, ulcerative colitis, Crohn's disease,irritable bowel syndrome and emesis, including acute, delayed,post-operative, late phase or anticipatory emesis such as emesis inducedby chemotherapy, radiation, toxins, viral or bacterial infections,pregnancy, vestibular disorders, motion, surgery, migraine, opioidanalgesics, and variations in intercranial pressure, in particular, forexample, drug or radiation induced emesis or post-operative nausea andvomiting; disorders of bladder function such as cystitis, bladderdetrusor hyper-reflexia and incontinence; fibrosing and collagendiseases such as scleroderma and eosinophilic fascioliasis; disorders ofblood flow caused by vasodilation and vasospastic diseases such asangina, migraine and Reynaud's disease; and pain or nociception, forexample, dental pain and that attributable to or associated with any ofthe foregoing conditions, especially the transmission of pain inmigraine.

Hence, the compounds of the present invention may be of use in thetreatment of physiological disorders associated with excessivestimulation of tachykinin receptors, especially neurokinin-1 receptors,and as neurokinin-1 antagonists for the control and/or treatment of anyof the aforementioned clinical conditions in mammals, including humans.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment ofemesis, including acute, delayed, post-operative, late phase oranticipatory emesis, such as emesis or nausea induced by chemotherapy,radiation, toxins, such as metabolic or microbial toxins, viral orbacterial infections, pregnancy, vestibular disorders, motion,mechanical stimulation, gastrointestinal obstruction, reducedgastrointestinal motility, visceral pain, psychological stress ordisturbance, high altitude, weightlessness, opioid analgesics,intoxication, resulting for example from consumption of alcohol,surgery, migraine, and variations in intercranial pressure. Mostespecially, the compounds of formula (I) are of use in the treatment ofemesis induced by antineoplastic (cytotoxic) agents including thoseroutinely used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulphonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in "Nausea and Vomiting: Recent Research andClinical Advances", Eds. J. Kuucharczyk et al, CRC Press Inc., BocaRaton, Fla., USA (1991) pages 177-203, especially page 188. Commonlyused chemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil R. J. Gralla et al in Cancer TreatmentReports (1984) 68(1), 163-172!.

The compounds of formula (I) are also of use in the treatment of emesisinduced by radiation including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operative nausea and vomiting.

It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use for the reliefof emesis. Such combined preparations may be, for example, in the formof a twin pack.

A further aspect of the present invention comprises the compounds offormula (I) in combination with a 5-HT₃ antagonist, such as ondansetron,granisetron or tropisetron, or other anti-emetic medicaments, forexample, a dopamine antagonist such as metoclopramide or GABAs receptoragonists such as baclofen. Additionally, a compound of formula (I) maybe administered in combination with an anti-inflammatory corticosteroid,such as dexamethasone, triamcinolone, triamcinolone acetonide,flunisolide, budesonide, or others such as those disclosed in U.S. Pat.Nos. 2,789.118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359,3,928,326 and 3,749,712. Dexamethasone (Decadron™) is particularlypreferred. Furthermore, a compound of formula (I) may be administered incombination with a chemotherapeutic agent such as an alkylating agent,antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as describedabove. In general, the currently available dosage forms of the knowntherapeutic agents for use in such combinations will be suitable.

When tested in the ferret model of cisplatin-induced emesis described byF. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250, R5-R6, thecompounds of the present invention were found to attenuate the retchingand vomiting induced by cisplatin.

The compounds of formula (I) are also particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example, neuropathy, such as diabeticand chemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis, headache and especiallymigraine.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor antagonist or tachykinin antagonist which acts at NK-2receptors. The compound of formula (I) and the bronchodilator may beadministered to a patient simultaneously, sequentially or incombination.

Likewise, a compound of the present invention may be employed with aleukotriene antagonists, such as a leukotriene D₄ antagonist such as acompound selected from those disclosed in European patent specificationnos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and5,270,324. This combination is particularly useful in the treatment ofrespiratory diseases such as asthma, chronic bronchitis and cough.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,especially sumatriptan.

Likewise, for the treatment of behavioural hyperalgesia, a compound ofthe present invention may be used in conjunction with an antagonist ofN-methyl D-aspartate (NMDA), such as dizocilpine.

For the treatment or prevention of inflammatory conditions in the lowerurinary tract, especially cystitis, a compound of the present inventionmay be used in conjunction with an antiinflammatory agent such as abradykinin receptor antagonist.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis using an injectable formulation, a suitabledosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

According to one general process (A), the compounds of formula (I) maybe prepared from compounds of formula (II) ##STR7## wherein R¹, R², R³,R⁴, R⁵, R^(9a), R^(9b) and Y are as defined in relation to formula (I)by reaction with formaldehyde followed by the desired amine of formulaHNR⁶ R⁷, in the presence of a suitable catalyst, for example, copper (I)chloride.

This reaction may be performed in a conventional manner, for example ina solvent such as an ether, for example, dioxan, at an elevatedtemperature between 50° C. and 100° C., for example, at about 80° C.

According to another process (B), the compounds of formula (I) may beprepared from compounds of formula (III) ##STR8## wherein R¹, R², R³,R⁴, R⁵, R^(9a), R^(9b) and Y are as defined in relation to formula (I)and Hal is a halogen atom such as chlorine, bromine or iodine, byreaction with an amine of formula HNR⁶ R⁷ or imidazole (preferably inthe form of its sodium salt) in the presence of a base.

Suitable bases of use in the reaction include alkali metal carbonatessuch as, for example, potassium carbonate. The reaction is convenientlyeffected in a suitable organic solvent such as, for example,N,N-dimethylformamide, conveniently at room temperature.

According to another process (C), compounds of formula (I) may beprepared by the interconversion of a compound of formula (IV): ##STR9##using alkyl halides of the formula R⁶ -Hal and R⁷ -Hal, or a suitabledihalide designed to form a saturated heterocyclic ring, wherein R⁶ andR⁷ are as previously defined, and Hal represents a halogen atom such aschlorine, bromine or iodine, in the presence of a base.

Suitable bases of use in the reaction include alkali metal carbonates,such as, for example, potassium carbonate.

The reaction is conveniently effected in a suitable organic solvent,such as, for example, N,N-dimethylformamide, conveniently at roomtemperature.

Suitable dihalides for forming a saturated heterocyclic ring include,for example, Hal-(CH₂)₄ -Hal (to give a pyrrolidino ring), Hal-(CH₂)₂O(CH₂)₂ Hal (to give a morpholino ring), or Hal-(CH₂)₂ NR⁸ (CH₂)₂ Hal(to give a piperazino ring).

Intermediates of formula (IV) may be prepared from intermediates offormula (II) or (III) by reaction with ammonia according to the methodof either process (A) or process (B).

The compounds of formula (II) may be prepared from an intermediate offormula (V) ##STR10## by reaction with a compound of formula (VI)

    HC.tbd.C--CH.sub.2 Hal                                     (VI)

where Hal is as previously defined, in a conventional manner, forexample in an organic solvent such as dimethylformamide in the presenceof an acid acceptor such as potassium carbonate.

Similarly, the compounds of formula (III) may be prepared by thedropwise addition of an intermediate of formula (V) to a compound orformula (VII)

    HalCHC.sub.2 --C.tbd.C--CH.sub.2 Hal                       (VII)

where Hal is as previously defined, in the presence of a base aspreviously described.

The compounds of formula (V) may be prepared as shown in the followingscheme in which Ar¹ represents the R¹, R², R³ substituted phenyl group;Ar² represents the R⁴, R⁵ substituted phenyl group and Ph representsphenyl: ##STR11##

The following references describe methods which may be applied by theskilled worker to the chemical synthesis set forth above once theskilled worker has read the (disclosure herein.

(i) D. A. Evans et al., J. Am. Chem. Soc., 112, 4011 (1990).

(ii) Yanagisawa, I. et al., J. Med. Chem., 27, 849 (1984).

(iii) Duschinsky, R. et al., J. Am. Chem. Soc., 70, 657 (1948).

(iv) Tebbe F. N. et al., J. Am. Chem. Soc., 100, 3611 (1978).

(v) Petasis, N. A. et al., J. Am. Chem. Soc., 112, 6532 (1990).

(vi) Takai, K. et al., J. Org. Chem., 52, 4412 (1987).

The Examples disclosed herein produce predominently the preferredisomers. The unfavoured isomers are also produced on minor components.If desired they may be isolated and employed to prepare the variousstereoisomers in conventional manner, for example chromatography usingan appropriate chiral column. However, the skilled worker willappreciate that although the Examples have been optimized to theproduction of the preferred isomers, variation in solvent, reagents,chromatography etc can be readily employed to yield the other isomers.

L-Selectride is lithium tri-sec-butylborohydride.

Where they are not commercially available, the intermediates above maybe prepared by the procedures described in the accompanying Examples orby alternative procedures which will be readily apparent to one skilledin the art.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds were found to be active with IC50 at the NK1receptor of less than 100 nM.

The following Examples illustrate the preparation of compounds accordingto the present invention:

DESCRIPTION 1 (S)-(4-Fluorophenyl)glcyine

Via Chiral Synthesis

Step A: 3-(4-Fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 L 3-necked flask, equipped with a septum, nitrogeninlet, thermometer, and a magnetic stirring bar, was flushed withnitrogen and charged with a solution of 5.09 g (33.0 mmol) of4-fluorophenylacetic acid in 100 ml of anhydrous ether. The solution wascooled to -10° C. and treated with 5.60 ml (40.0 mmol) of triethylaminefollowed by 4.30 ml (35.0 mmol) of trimethylacetyl chloride. A whiteprecipitate formed immediately. The resulting mixture was stirred at-10° C. for 40 minutes, then cooled to -78° C.

An oven-dried, 250 ml round bottom flask, equipped with a septum and amagnetic stirring bar, was flushed with nitrogen and charged with asolution of 5.31 g (30.0 mmol) of 4-(S)-benzyl-2-oxazolidinone in 40 mlof dry THF. The solution was stirred in a dry ice/acetone bath for 10minutes, then 18.8 ml of 1.6M n-butyllithium solution in hexanes wasslowly added. After 10 minutes, the lithiated oxazolidinone solution wasadded, via cannula, to the above mixture in the 3-necked flask. Thecooling bath was removed from the resulting mixture and the temperaturewas allowed to rise to 0° C. The reaction was quenched With 100 ml ofsaturated aqueous ammonium chloride solution, transferred to a 1 lflask, and the ether and THF were removed in vacuo. The concentratedmixture was partitioned between 300 ml of methylene chloride and 50 mlof water and the layers were separated. The organic layer was washedwith 100 ml of 2N aqueous hydrochloric acid solution, 300 ml ofsaturated aqueous sodium bicarbonate solution, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography on 400 g ofsilica gel using 3:2 v/v hexanes/ether as the eluant afforded 8.95 g ofan oil that slowly solidified on standing. Recrystallisation from 10:1hexanes/ether afforded 7.89 g (83%) of the title compound as a whitesolid: mp 64°-66° C. MS (FAB): m/z 314 (M⁺ +H, 100%), 177 (M--ArCH₂CO+H, 85%). 1H NMR (400 MHz, CDCl₃) δ2.76 (1H, dd, J=13.2, 9.2 Hz), 3.26(dd, J=13.2, 3.2 Hz), 4.16-4.34 (4H, m), 4.65 (1H, m), 7.02-7.33 (9H,m).

Analysis Calcd. for C₁₈ H₁₆ FNO₃ : C, 69.00; H, 5.15; N, 4.47; F, 6.06;Found: C, 68.86; H, 5.14; N, 4.48; F, 6.08%.

Step B:3-((S)-Azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone

An oven-dried, 1 l 3-necked flask, equipped with a septum, nitrogeninlet, thermometer, and a magnetic stirring bar, was flushed withnitrogen and charged with a solution of 58.0 ml of 1M potassiumbis(trimethylsilyl)amide solution in toluene and 85 ml of THF and wascooled to -78° C. An oven-dried 250 ml round-bottomed flask, equippedwith a septum and a magnetic stirring bar, was flushed with nitrogen andcharged with a solution of 7.20 g (23.0 mmol) of3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone (from Step A) in40 ml of THF. The acyl oxazolidinone solution was stirred in a dryice/acetone bath for 10 minutes, then transferred, via cannula, to thepotassium bis(trimethylsilyl)amide solution at such a rate that theinternal temperature of the mixture was maintained below -70° C. Theacyl oxazolidinone flask was rinsed with 15 ml of THF and the rinse wasadded, via cannula, to the reaction mixture and the resulting mixturewas stirred at -78° C. for 30 minutes. An oven-dried, 250 mlround-bottomed flask, equipped with a septum and a magnetic stirringbar, was flushed with nitrogen and charged with a solution of 10.89 g(35.0 mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40 ml of THF.The azide solution was stirred in a dry ice/acetone bath for 10 minutes,then transferred, via cannula, to the reaction mixture at such a ratethat the internal temperature of the mixture was maintained below -70°C. After 2 minutes, the reaction was quenched with 6.0 ml of glacialacetic acid, the cooling bath was removed and the mixture was stirred atroom temperature for 18 hours. The quenched reaction mixture waspartitioned between 300 ml of ethyl acetate and 300 ml of 50% saturatedaqueous sodium bicarbonate solution. The organic layer was separated,dried over magnesium sulfate, and concentrated in vacuo. Flashchromatography on 500 g of silica gel using 2:1 v/v, then 1:1 v/vhexanes/methylene chloride as the eluant afforded 5.45 g (67%) of thetitle compound as an oil. IR Spectrum (neat, cm⁻¹): 2104, 1781, 1702. ¹H NMR (400 MHz, CDCl₃) δ2.86 (1H, dd, J=13.2, 9.6 Hz), 3.40 (1H, dd,J=13.2, 3.2 Hz), 4.09-4.19 (2H, m), 4.62-4.68 (1H, m), 6.14 (1H, s),7.07-7.47 (9H, m).

Analysis Calcd. for C₁₈ H₁₅ FN₄ O₃ : C 61.01; H, 4.27; N, 15.81; F,5.36; Found: C, 60.99; H, 4.19; N, 15.80; F, 5.34%.

Step C: (S)-Azido-(4-fluorophenyl)acetic acid

A solution of 5.40 g (15.2 mmol) of3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone (fromStep B) in 200 ml of 3:1 v/v THF/water was stirred in an ice bath for 10minutes. 1.28 g (30.4 mmol) of lithium hydroxide monohydrate was addedin one portion and the resulting mixture was stirred cold for 30minutes. The reaction mixture was partitioned between 100 ml ofmethylene chloride and 100 ml of 25% saturated aqueous sodiumbicarbonate solution and the layers were separated. The aqueous layerwas washed with 2×100 ml of methylene chloride and acidified to pH 2with 2N aqueous hydrochloric acid solution. The resulting mixture wasextracted with 2×100 ml of ethyl acetate; the extracts were combined,washed with 50 ml of saturated aqueous sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo to afford 2.30 g (77%)of the title compound as an oil that was used in the following stepwithout further purification. IR Spectrum (neat, cm⁻¹): 2111, 1724. ¹ HNMR (400 MHz, CDCl₃) δ5.06 (1H, s), 7.08-7.45 (4H, m), 8.75 (1H, br s).

Step D: (S)-(4-Fluorophenyl)glycine

A mixture of 2.30 g (11.8 mmol) of (S)-azido-(4-fluorophenyl)acetic acid(from Step C), 2.50 mg 10% palladium on carbon catalyst and 160 ml 3:1v/v water/acetic acid was stirred under an atmosphere of hydrogen for 18hours. The reaction mixture was filtered through Celite and the flaskand filter cake were rinsed well with about 1 liter of 3:1 v/vwater/acetic acid. The filtrate was concentrated in vacuo to about 50 mlof volume. 300 ml of toluene was added and the mixture concentrated toafford a solid. The solid was suspended in 1:1 v/v methanol/ether,filtered and dried to afford 1.99 g (100%) of the title compound. ¹ HNMR (400 MHz, D₂ O+NaOD) δ3.97 (1H, s), 6.77 (2H, app t, J=8.8 Hz), 7.01(2H, app t, J=5.6 Hz).

Via Resolution

Step A' (4-Fluorophenyl)acetyl chloride

A solution of 150 g (0.974 mol) of 4-(fluorophenyl)acetic acid and 1 mlof N,N-dimethylformamide in 500 ml of toluene at 40° C. was treated with20 ml of thionyl chloride and heated to 40° C. An additional 61.2 ml ofthionyl chloride was added dropwise over 1.5 hours. After the addition,the solution was heated at 50° C. for 1 hour, the solvent was removed invacuo and the residual oil was distilled at reduced pressure (1.5 mmHg)to afford 150.4 g (89.5%) of the title compound, bp=68°-70° C.

Step B': Methyl 2-bromo-3-(4-fluorophenyl)acetate

A mixture of 150.4 g (0.872 mol) of 4-(fluorophenyl)acetyl chloride(from Step A') and 174.5 g (1.09 mol) of bromine was irradiated at40°-50° C. with a quartz lamp for 5 hours. The reaction mixture wasadded dropwise to 400 ml of methanol and the solution was stirred for 16hours. The solvent was removed in vacuo and the residual oil wasdistilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of thetitle compound, bp=106°-110° C.

Step C': Methyl (±)-(4-fluorophenyl)glycine

A solution of 24.7 g (0.1 mol) of methyl2-bromo-2-(4-fluorophenyl)acetate (from Step B') and 2.28 g (0.01 mol)of benzyl triethylammonium chloride in 25 ml of methanol was treatedwith 6.8 g (0.105 mol) of sodium azide and the resulting mixture wasstirred for 20 hours at room temperature. The reaction mixture wasfiltered; the filtrate was diluted with 50 ml of methanol andhydrogenated in the presence of 0.5 g of 10% Pd/C at 50 psi for 1 hour.The solution was filtered and the solvent removed in vacuo. The residuewas partitioned between 10% aqueous sodium carbonate solution and ethylacetate. The organic phase was washed with water, saturated aqueoussodium chloride solution dried over magnesium sulfate and concentratedin vacuo to afford 9.8 g of the title compound as an oil.

Step D': Methyl (S)-(4-fluorophenyl)glycinate

A solution of 58.4 g of methyl (±) 4-(fluorophenyl)glycinate (from StepC') in 110 ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6g (0.0799 mol) of O,O'-(+)-dibenzoyltartaric acid ((+)-DBT) (28.6 g,0.0799 mol) in 110 ml of 7:1 v/v ethanol:water and the resultingsolution was allowed to age at room temperature. Ethyl acetate (220 ml)was added after crystallisation was complete and the resulting mixturewas cooled to -20° C. and filtered to afford 32.4 g of methyl(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=93.2%). The motherliquors were concentrated in vacuo and the free base was liberated bypartitioning between ethyl acetate and aqueous sodium carbonatesolution. A solution of free base, so obtained, in 110 ml of 7:1 v/vethanol/water was mixed teeth a solution of 28.6 g (0.0799 mol) ofO,O'-(-)-dibenzoyltartaric acid ((-)-DBT) (28.6 g, 0.0799 mol) in 110 mlof 7:1 v/v ethanol:water and the resulting solution was allowed to ageat room temperature. Ethyl acetate (220 ml) was added aftercrystallisation was complete and the resulting mixture was cooled to-20° C. and filtered to afford 47.0 g of methyl(R)-(4-fluorophenyl)glycinate, (-)-DBT salt (ee=75.8%). Recycling of themother liquors and addition of (+)-DBT gave a second crop of 7.4 g of(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=96.4%). The two crops ofthe (S)-amino ester (39.8 g) were combined in 200 ml of 7:1 v/vethanol/water, heated for 30 minutes and cooled to room temperature.Addition of ethyl acetate, cooling, and filtration afforded 31.7 g of(S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee>98%). Enantiomericexcess was determined by chiral HPLC (Crownpak CR(+) 5% MeOH in aq HClO₄pH2 1.5 ml/min 40° C. 200 nm).

A mixture of 17.5 g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt and32 ml of 5.5N HCl (32 ml) was heated at reflux for 1.5 hours. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin 40 ml of water. The aqueous solution was washed (3×30 ml of ethylacetate) and the layers were separated. The pH of the aqueous layer wasadjusted to 7 using ammonium hydroxide and the precipitated solid wasfiltered to afford 7.4 g of the title compound (ee=98.8%).

DESCRIPTION 2 4-Benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone

Step A: N-Benzyl-(S)-(4-fluorophenyl)glycine

A solution of 1.87 g (11.05 mmol) of (S)-(4-fluorophenyl)-glycine (fromDescription 1) and 1.12 ml (11.1 mmol) of benzaldehyde in 11.1 ml of 1Naqueous sodium hydroxide solution and 11 ml of methanol at 0° C. wastreated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bathwas removed and the resulting mixture was stirred at room temperaturefor 30 minutes. Second portions of benzaldehyde (1.12 ml (11.1 mmol))and sodium borohydride (165 mg (4.4 mmol) were added to the reactionmixture and stirring was continued for 1.5 hours. The reaction mixturewas partitioned between 100 ml of ether and 50 ml of water and thelayers were separated. The aqueous layer was separated and filtered toremove a small amount of insoluble material. The filtrate was acidifiedto pH 5 with 2N aqueous hydrochloric acid solution and the solid thathad precipitated was filtered, rinsed well with water, then ether, anddried to afford 1.95 g of the title compound. ¹ H NMR (400 MHz, D₂O+NaOD) δ3.33 (2H, AB q, J=8.4 Hz), 3.85 (1H, s), 6.79-7.16 (4H, m).

Step B: 4-Benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone

A mixture of 1.95 g (7.5 mmol) of N-benzyl (S)-(4-fluorophenyl)glycine,3.90 ml (22.5 mmol) of N,N-diisopropyl-ethylamine, 6.50 ml (75.0 mmol)of 1,2-dibromoethane and 40 ml of N,N-dimethylformamide was stirred at100° C. for 20 hours (dissolution of all solids occurred on warming).The reaction mixture was cooled and concentrated in vacuo. The residuewas partitioned between 250 ml of ether and 100 ml of 0.5N potassiumhydrogen sulfate solution and the layers were separated. The organiclayer was washed with 100 ml of saturated aqueous sodium bicarbonatesolution, 3×150 ml of water, dried over magnesium sulfate, andconcentrated in vacuo. Flash chromatography on 125 g of silica gel using3:1 v/v hexanes/ether as the eluant afforded 1.58 g (74%) of the titlecompound as an oil. ¹ H NMR (400 MHz, CDCl₃) δ2.65 (1H, dt, J=3.2, 12.8Hz), 3.00 (1H, dt, J=12.8, 2.8 Hz), 3.16 (1H, d, J=13.6 Hz), 3.76 (1H,d, J=13.6 Hz), 4.24 (1H, s), 4.37 (1H, dt, J=13.2, 3.2 Hz), 4.54 (1H,dt, J=2.8, 13.2 Hz), 7.07-7.56 (9H, m).

DESCRIPTION 34-Benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluorophenyl)morpholine

A solution of 2.67 g (10.0 mmol) of4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone (Description 2) in 40 mlof dry THF was cooled to -78° C. The cold solution was treated with 12.5ml of 1.0 ml L-Selectride® solution in THF, maintaining the internalreaction temperature below -70° C. The resulting solution was stirredcold for 45 minutes and the reaction was charged with 3.60 ml(20.0 mmol)of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellowmixture was stirred cold for 30 minutes and the reaction was quenchedwith 50 ml of saturated aqueous sodium bicarbonate solution. Thequenched mixture was partitioned between 300 ml of ether and 50 ml ofwater and the layers were separated. The organic layer was dried overmagnesium sulfate. The aqueous layer was extracted with 300 ml of ether;the extract was dried and combined with the original organic layer. Thecombined organics were concentrated in vacuo. Flash chromatography on150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded4.06 g (80%) of the title compound as a solid.

¹ H NMR (200 MHz, CDCl₃) δ2.50 (1H, dt, J=3.4, 12.0 Hz), 2.97 (¹ H, appd, J=12.0 Hz), 2.99 (1H, d, J=13.6 Hz), 3.72-3.79 (1H, m), 3.82 (1H, d,J=2.6 Hz), 4.00 (1H, d, J=13.6 Hz), 4.20 (dt, J=2.4, 11.6 Hz), 6.22 (1H,d, J=2.6 Hz), 7.22.7.37 (7H, m), 7.57 (2H, app d, J=6.8 Hz), 8.07 (1H,s), 8.47 (2H, s). MS (FAB) m/z 528 (M+H, 25%), 270 (100%).

Analysis Calcd. for C₂₆ H₂₀ F₇ NO₃ : C, 59.21; H, 3.82; N, 2.66; F,25.21; Found: C, 59.06; H, 4.05; N. 2.50; F, 25.18%.

DESCRIPTION 44-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)morpholine

Step A: Dimethyl titanocene

A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 ml ofether in the dark at 0° C. was treated with 17.5 ml of 1.4Mmethyllithium solution in ether maintaining the internal temperaturebelow 5° C. The resulting yellow/orange mixture was stirred at roomtemperature for 30 minutes and the reaction was quenched by slowlyadding 25 g of ice. The quenched reaction mixture was diluted with 50 mlof ether and 25 ml of water and the layers were separated. The organiclayer was dried over magnesium sulfate and concentrated in vacuo toafford 2.03 g (98%) of the title compound as a light-sensitive solid.The dimethyl titanocene could be stored as a solution in toluene at 0°C. for at least 2 weeks without apparent chemical degradation. ¹ H NMR(200 MHz, CDCl₃) δ-0.15 (6H, s), 6.06 (10H, s).

Step B:4-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)Phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)morpholine

A solution of the compound of Description 3 (2.50 g, 4.9 mmol) and 2.50g (12.0 mmol) of dimethyl titanocene (from Step A) in 35 ml of 1:1 v/vTHF/toluene was stirred in an oil bath at 80° C. for 16 hours. Thereaction mixture was cooled and concentrated in vacuo. Flashchromatography on 150 g of silica gel using 3:1 v/v hexanes/methylenechloride as the eluant afforded 1.71 g (69%) of the title compound as asolid. An analytical sample was obtained via recrystallisation fromisopropanol: ¹ H NMR (400 MHz, CDCl₃) δ2.42 (1H, dt, J=3.6, 12.0 Hz),2.90 (1H, app d, J=12.0 Hz), 2.91 (1H, d, J=13.6 Hz), 3.62-3.66 (1H, m),3.72 (1H, d, J=2.6 Hz), 3.94 (1H, d, J=13.6 Hz), 4.09 (1H, dt, J=2.4,12.0 Hz), 4.75 (1H, d, J=3.2 Hz), 4.82 (1H, d, J=3.2 Hz), 5.32 (1H, d,J=2.6 Hz), 7.09 (2H, t, J=8.8 Hz), 7.24-7.33 (5H, m), 7.58-7.62 (2H, m),7.80 (1H, s), 7.90 (2H, s);

MS (FAB) 526 (M+H, 75%), 270 (100%).

Analysis Calcd. for C₂₇ H₂₂ F₇ NO₂ : C, 61.72; H, 4.22; N, 2.67; F,25.31; Found: C, 61.79; H, 4.10; N, 2.65; F, 25.27%.

DESCRIPTION 52-(R)-(1(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 4 (4.0 g) was dissolved in ethyl acetate (50ml) and isopropanol (16 ml). To this solution was added palladium oncharcoal (1.5 g) and the mixture was hydrogenated at 40 psi for 36 h.The catalyst was removed by filtration through Celite and the solventswere removed in vacuo. The residue was purified by flash chromatographyon silica using 100% ethyl acetate and then 1-10% methanol in ethylacetate. This afforded isomer A 500 mg (15%) and isomer B 2.6 g (80%) asclear oils--isomer B crystallised on standing. For the title compound: ¹H NMR (400 MHz, CDCl₃) δ1.16 (3H, d, J=6.8 MHz), 1.80 (1H, br s), 3.13(1H, dd, J=3.2, 12.4 Hz), 3.23 (1H, dt, J=3.6, 12.4 Hz), 3.63 (1H, dd,J=2.4, 11.2 Hz), 4.01 (1H, d, J=2.4 Hz), 4.13 (1H, dt, J=3.2, 12.0 Hz),4.42 (1H, d, J=2.4 Hz), 4.19 (1H, q, J=6.8 Hz), 7.04-7.09 (2H, m),7.27-7.40 (4H, m), 7.73 (1H

MS (FAB) 438 (M+H, 75%), 180 (100%).

HCl salt formation. To a solution of the free base (0.77 g) in diethylether (10 ml) was added 1M-HCl in methanol (1.75 ml). The solution wasevaporated to dryness and on addition of diethyl ether crystals formed.The solution was filtered and the residue washed with diethyl ether togive the title compound hydrochloride salt mp 248°-250° C.

Analysis Calcd. for C₂₀ H₁₈ F₇ NO₂.HCl: C, 50.70; H, 4.04; N, 2.96; Cl,7.48; Found: C, 50.46; H, 3.85; N, 3.01; Cl, 7.31%.

DESCRIPTION 62-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-chlorobut-2-ynyl)-3-(S)-(4-fluorophenyl)morpholine

A solution of the product of Description 5 (free base, 5 g) inN,N-dimethylformamide (20 ml) was slowly added to a heated (50° C.)solution of 1,4-dichlorobut-2-yne (2.2 ml) and potassium carbonate (4.8g) in N,N-dimethylformamide (20 ml). The solution was heated for afurther 5 h at 50° C. and then the solvent removed in vacuo. To theresidue was added water (400 ml) and the product extracted into ethylacetate (3×150 ml). The combined organic phase was washed with water,saturate brine and dried (MgSO4). The solvent was removed in vacuo andthe residue chromatographed on silica gel (eluting with 10% ethylacetate in petroleum ether bp 60°-80° C.) to give the title compound asa colourless oil.

¹ H NMR (250 MHz, CDCl₃) δ1.41 (3H, d, J=6.6 Hz), 2.80 (1H, app. t,J=10.8 Hz), 2.87 (1H, td, J=3.5 Hz, 11.7 Hz), 3.22 (2H, t, J=1.9 Hz),3.52 (1H, d, J=2.8 Hz), 3.68 (1H, d, J=1.4 Hz, 11.1 Hz), 4.00 (2H, t,J=1.9 Hz), 4.22-4.32 (2H, m), 4.81 (1H, q, J=6.6 Hz), 6.96 (2H, t, J=8.7Hz), 7.10 (2H, s), 7.31 (2H, br s), 7.56 (1H, s). m/z (CI⁺) 524 (M+H,100%).

DESCRIPTION 72-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(prop-2-ynyl)morpholine

Propargyl bromide (1.9 ml) was added to a stirred mixture of thecompound of Description 5 (5 g) and potassium carbonate (4.76 g) in drydimethylformamide at 23° C. After 15 min the reaction mixture wasdiluted with water (250 ml) and extracted with ethyl acetate (3×100 ml).The combined organic phases were washed with brine (1×100 ml) then dried(K₂ CO₃) and concentrated to leave an oil. This was purified bychromatography on silica using ethyl acetate in hexane (1:9 then 1:4) aseluent to afford the title compound as an oil. ¹ H NMR (250 MHz, CDCl₃)δ1.50 (3H, d, J=6.6 Hz), 2.21 (1H, s), 2.84 (1H, d, J=11.1 Hz), 2.97(1H, td, J=3.2, 11.7 Hz), 3.26 (2H, d, J=1.8 Hz), 3.62 (1H, d, J=2.2Hz), 3.71 (1H, dd, J=2.3, 11.1 Hz), 4.33 (2H, m), 4.89 (1H, q, J=6.6Hz), 7.03 (2H, t, J=8.6 Hz), 7.18 (2H, s), 7.38 (2H, br s), 7.63 (1H,s). MS (CI+) m/z 476 (MH, 100%).

DESCRIPTION 84-Benzyl-3-(S)-(4-fluorophenyl)-2-(R)-(3-fluoro-5-(trifluoromethyl)benzoyloxy)morpholine

The title compound was prepared from the reaction of the compound ofDescription 2 with 3-fluoro-5-(trifluoromethyl)benzoyl chlorideaccording to the procedure illustrated in Description 3. ¹ H NMR (360MHz, CDCl₃) δ2.50 (1H, dt, J=3.3, 12.0 Hz), 2.96 (1H, d, J=12.0 Hz),2.98 (1H, d, J=13.6 Hz), 3.75 (1H, dd, J=1.7, 11.5 Hz), 3.80 (1H, d,J=2.5 Hz), 3.92 (1H, d, J=13.6 Hz), 4.19 (1H, dt, J=2.1, 12.0 Hz), 6.20(1H, d, J=2.5 Hz), 6.99 (2H, t, J=8.7 Hz), 7.2-7.37 (5H, m), 7.51-7.55(3H, m), 7.89 (1H, d, J=8.4 Hz), 8.09 (1H, s). MS (CI+) m/z 478 (M⁺ +1,100%).

Analysis Calcd. for C₂₅ H₂₀ F₅ NO₃ : C, 62.88; H, 4.23; N, 2.93; Found:C, 62.59; H, 4.03; N, 3.07%.

DESCRIPTION 94-Benzyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(3-fluoro-5-(trifluoromethyl)phenyl)ethenyloxy)morpholine

The title compound was prepared in 85% yield from the compound ofDescription 6 according to the procedure illustrated in Description 4.

¹ H NMR (360 MHz, CDCl₃) δ2.42 (1H, dt, J=3.6, 12.0 Hz), 2.90 (1H, d,J=12.0 Hz), 2.91 (1H, d, J=13.6 Hz), 3.60-3.62 (1H, m), 3.72 (1H, d,J=2.6 Hz), 3.92 (1H, d, J=13.6 Hz), 4.09 (1H, dt, J=2.4, 12.0 Hz), 4.67(1H, d, J=2.9 Hz), 4.76 (1H, d, J=2.9 Hz), 5.28 (1H, d, J=2.6 Hz), 7.07(2H, t, J=8.7 Hz), 7.2-7.37 (7H, m), 7.53 (1H, s), 7.57-7.61 (2H, m). MS(CI+) 476 (M+1, 100%).

DESCRIPTION 103-(S)-(4-Fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine

The compound of Description 9 was hydrogenated according to the methodillustrated in Description 5. This afforded a mixture of 2 epimericproducts isomer A and isomer B (the major product) as clear oils. Forthe title compound: ¹ H NMR (360 MHz, CDCl₃) δ1.42 (3H, d, J=6.6 Hz),1.91 (1H, s), 3.11 (1H, dd, J=3.2, 12.4 Hz), 3.22 (1H, dt, J=3.6, 12.4Hz), 3.58-3.62 (1H, m), 4.01 (1H, d, J=2.3 Hz), 4.11 (1H, dt, J=3.2,12.0 Hz), 4.41 (1H, d, J=2.3 Hz), 4.80 (1H, q, J=6.6 Hz), 6.41 (1H, d,J=9.2 Hz), 6.86 (1H, s), 7.02 (2H, t, J=8.7 Hz), 7.08 (2H, d, J=9.2 Hz),7.21-7.26 (2H, m). MS (CI+) m/z 387 (M+1, 100%).

Analysis Calcd. for C₁₉ H₁₈ F₅ NO₂ : C, 58.91; H, 4.69; N, 3.62; Found:C, 58.88; H, 4.81; N, 3.76%.

DESCRIPTION 114-(4-Chlorobut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine

This compound was prepared from the compound of Description 10 followingthe procedure illustrated in Description 6. ¹ H NMR (250 MHz, CDCl₃)δ1.43 (3H, d, J=6.6 Hz), 2.80-2.90 (1H, m), 2.94 (1H, dt, J=11.7, 3.5Hz), 3.32 (2H, t, J=2.0 Hz), 3.60 (1H, d, J=2.8 Hz), 3.67-3.74 (1H, m),4.14 (2H, d, J=2.0 Hz), 4.33 (2H, dt, J=11.3, 3.3 Hz), 4.78 (1H, q,J=6.6 Hz), 6.39 (1H, d, J=9.1 Hz), 6.81 (1H, s), 7.01-7.08 (3H, m), 7.36(2H, br s). MS (CI+) m/z 474/476 (M+1, 100/35%).

DESCRIPTION 124-Benzyl-3-(S)-(4-fluorophenyl)-2-(R)-(3-(trifluoromethyl)benzoyloxy)morpholine

The title compound was prepared from the reaction of the compound ofDescription 2 with 3-(trifluoromethyl)benzoyl chloride according to theprocedure illustrated in Description 3. ¹ H NMR (360 MHz, CDCl₃) δ2.48(1H, dt, J=12.0, 3.5 Hz), 2.94 (1H, d, J=13.6 Hz), 3.73 (1H, app.d,J=11.4 Hz), 3.78 (1H, d, J=2.7 Hz), 3.91 (1H, d, J=13.6 Hz), 4.21 (1H,dt, J=11.7, 2.4 Hz), 6.20 (1H, d, J=2.8 Hz), 6.97 (2H, t, J=8.7 Hz),7.25-7.37 (5H, m), 7.53 (2H, m), 7.61 (1H, t, J=7.8 Hz), 7.84 (1H, d,J=8.0 Hz), 8.21 (1H, d, J=7.8 Hz), 8.30 (1H, s). MS (CI⁺) m/z 460 (M+1,100%).

DESCRIPTION 134-Benzyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(3-(trifluoromethyl)phenyl)ethenyloxy)morpholine

The title compound was prepared from the compound of Description 12according to the procedure illustrated in Description 4. ¹ H NMR (360MHz, CDCl₃) δ2.40 (1H, dt, J=11.9, 3.6 Hz), 2.87 (1H, app. d, J=11.8Hz), 2.89 (1H, d, J=13.5 Hz), 3.62 (1H, app.d, J=11.5 Hz), 3.70 (1H, d,J=2.7 Hz), 3.91 (1H, d, J=13.5 Hz), 4.12 (1H, dt, J=11.7, 2.4 Hz), 4.62(1H, d, J=2.7 Hz), 4.74 (1H, d, J=2.7 Hz), 5.30 (1H, d, J=2.7 Hz), 7.07(2H, t, J=8.7 Hz), 7.21-7.32 (5H, m), 7.40 (1H, t, J=7.8 Hz), 7.53-7.63(4H, m), 7.74 (1H, s). MS (CI⁺) m/z 458 (M+1, 100%).

DESCRIPTION 143-(S)-(4-Fluorophenyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine

The compound of Description 13 was hydrogenated according to the methodillustrated in Description 5. This afforded a mixture of 2 epimericproducts isomer A and isomer B in approximately equal mass as yellowoils. The title compound (isomer B): ¹ H NMR (360 MHz, CDCl₃) 1.43 (3H,d, J=6.6 Hz), 3.11 (1H, dd, J=12.6, 2.9 Hz), 3.22 (1H, dt, J=12.4, 3.7Hz), 3.60 (1H, dd, J=11.1, 2.8 Hz), 3.99 (1H, d, J=2.2 Hz), 4.13 (1H,dt, J=11.6, 3.2 Hz), 4.42 (1H, d, J=2.2 Hz), 4.81 (1H, q, J=6.6 Hz),6.84 (1H, d, J=7.8 Hz), 6.96-7.03 (3H, m), 7.16-7.27 (3H, m), 7.38 (1H,d, J=7.5 Hz). MS (CI⁺) m/z 370 (M+1, 100%).

Analysis Calcd. for C₁₉ H₁₉ F₄ NO₂ : C, 61.77; H, 5.20; N, 3.79; Found:C, 61.60; H, 5.16; N, 3.95%.

DESCRIPTION 154-(4-Chlorobut-2-ynyl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-trifluoromethyl)phenyl)ethoxy)morpholine

This compound was prepared from the compound of Description 14 followingthe procedure illustrated in Description 6. ¹ H NMR (360 MHz, CDCl₃)δ1.45 (3H, d, J=6.6 Hz), 2.85 (1H, br d, J=10.5 Hz), 2.93 (1H, dt,J=11.7, 3.6 Hz), 3.30 (2H, d, J=1.8 Hz), 3.58 (1H, d, J=2.7 Hz),3.67-3.72 (1H, m), 4.13 (2H, d, J=1.9 Hz), 4.31-4.39 (2H, m), 4.79 (1H,q, J=6.6 Hz), 6.81 (1H, d, J=7.8 Hz), 6.97-7.05 (4H, m), 7.15 (1H, t,J=7.7 Hz), 7.35 (2H, d, J=7.8 Hz). MS (CI+) m/z 456/458 (M+1, 100/38%).

DESCRIPTION 16 4-Benzyl-3-(S)-phenyl-2-morpholinone

Step A: N-Benzyl-(S)-phenylglycine

A solution of 1.51 g (10.0 mmol) of (S)-phenylglycine in 5 ml of 2Naqueous sodium hydroxide solution was treated with 1.0 ml (10.0 mmol) ofbenzaldehyde and stirred at room temperature for 20 minutes. Thesolution was diluted with 5 ml of methanol, cooled to 0° C., andcarefully treated with 200 mg (5.3 mmol) of sodium borohydride. Thecooling bath was removed and the reaction mixture was stirred at roomtemperature for 1.5 hours. The reaction was diluted with 20 ml of waterand extracted with 2×25 ml of methylene chloride. The aqueous layer wasacidified with concentrated hydrochloric acid to pH 6 and the solid thatprecipitated was filtered, washed with 50 ml of water, 50 ml of 1:1 v/vmethanol/ethyl ether and 50 ml of ether, and dried to afford 1.83 g(76%) of product, mp 230°-232° C.

Analysis Calcd. for C₁₅ H₁₅ NO₂ : C, 74.66; H, 6.27; N, 5.81; Found: C,74.17; H, 6.19; N, 5.86%.

Step B: 4-Benzyl-3-(S)-phenyl-2-morpholinone

A mixture of 4.00 g (16.6 mmol) of N-benzyl-(S)-phenylglycine (from StepA) 5.00 g (36.0 mmol) of potassium carbonate, 10.0 ml of1,2-dibromoethane and 25 ml of N,N-dimethylformamide was stirred at 100°C. for 20 hours. The mixture was cooled and partitioned between 200 mlof ethyl ether and 100 ml of water. The layers were separated and theorganic layer was washed with 3×50 ml of water, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography on 125 g of silica gel eluting with 9:1 v/v, then 4:1hexanes/ethyl ether to afford 2.41 g (54%) of the product as a solid, mp98°-100° C. ¹ H NMR (250 MHz, CDCl₃) δ2.54-2.68 (1H, m), 2.96 (1H, dt,J=12.8, 2.8 Hz), 3.14 (1H, d, J=13.3 Hz), 3.75 (1H, d, J=13.3 Hz), 4.23(1H, s), 4.29-4.37 (1H, m), 4.53 (dt, J=3.2, 11.0 Hz), 7.20-7.56 (10H,m). MS (FAB): m/z 268 (M+H; 100%).

DESCRIPTION 174-Benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-phenylmorpholine

A solution of 2.67 g (10.0 mmol) of the compound of Description 16 in 40ml of dry THF was cooled to -78° C. The cold solution was treated with12.5 ml of 1.0M L-Selectride® solution in THF, maintaining the internalreaction temperature below -70° C. The resulting solution was stirredcold for 45 minutes and the reaction was charged with 3.60 ml (20.0mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellowmixture was stirred cold for 30 minutes and the reaction was quenchedwith 50 ml of saturated aqueous sodium bicarbonate solution. Thequenched mixture was partitioned between 300 ml of ether and 50 ml ofwater and the layers were separated. The organic layer was dried overmagnesium sulfate. The aqueous layer was extracted with 300 ml of ether;the extract was dried and combined with the original organic layer. Thecombined organics were concentrated in vacuo. Flash chromatography on150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded4.06 g (80%) of the title compound as a solid. ¹ H NMR (200 MHz, CDCl₃)δ2.50 (1H, dt, J=3.4, 12.0 Hz), 2.97 (1H, app d, J=12.0 Hz), 2.99 (1H,d, J=13.6 Hz), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6 Hz), 4.00 (1H, d,J=13.6 Hz), 4.20 (dt, J=2.4, 11.6 Hz), 6.22 (1H, d, J=2.6 Hz), 7.22-7.37(7H, m), 7.57 (2H, app d, J=6.8 Hz), 8.07 (1H, s), 8.47 (2H, s).

Analysis Calcd. for C₂₆ H₂₁ F₆ NO₃ : C, 61.29; H, 4.16; N, 2.75; F,22.38; Found: C, 61.18; H, 4.14; N, 2.70; F, 22.13%.

DESCRIPTION 184-Benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-phenylmorpholine

A solution of 2.50 g (4.9 mmol) of the compound of Description 17 and2.50 g (12.0 mmol) of dimethyl titanocene (Description 4a), in 35 ml of1:1 v/v THF/toluene was stirred in an oil bath at 80° C. for 16 hours.The reaction mixture was cooled and concentrated in vacuo. Flashchromatography on 150 g of silica gel using 3:1 v/v hexanes/methylenechloride as the eluant afforded 1.71 g (69%) of the title compound as asolid. ¹ H NMR (400 MHz, CDCl₃) δ2.42 (1H, dt, J=3.6, 12.0 Hz), 2.89(app d, J=11.6 Hz), 2.92 (1H, d, J=13.6 Hz), 3.61-3.66 (1H, m), 3.73(1H, d, J=2.8 Hz), 4.00 (1H, d, J=13.6 Hz), 4.09 (1H, dt, J=2.4, 11.6Hz), 4.75 (1H, d, J=2.8 Hz), 4.79 (1H, d, J=2.8 Hz), 5.36 (1H, d, J=2.4Hz), 7.23-7.41 (7H, m), 7.63 (1H, app d, J=7.2 Hz), 7.79 (1H, s), 7.91(2H, s). MS (FAB) m/z 508 (M+1, 25%).

Analysis Calcd. for C₂₇ H₂₃ F₆ NO₂ ; C, 63.90; H, 4.57; N, 2.76; F,22.46; Found: C, 63.71; H, 4.53; N, 2.68; F, 22.66%.

DESCRIPTION 192-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine

A mixture of the compound of Description 18 (1.5 g) and 10% palladium oncarbon catalyst (750 mg) in a mixture of isopropanol/ethyl acetate (25ml, 3:2 v/v) was stirred under an atmosphere of hydrogen for 48 h. Thecatalyst was removed by filtration through celite and the reaction flaskand filter pad were rinsed with ethyl acetate (500 ml). The filtrate wasconcentrated in vacuo, flash chromatography afforded epimer A (106 mg)and epimer B (899 mg) as clear oils. The title compound, epimer B hadthe following analysis:

¹ H NMR (CDCl₃, 400 MHz) δ1.46 (3H, d, J=6.8 Hz), 1.92 (1H, br s), 3.13(1H, dd, J=3.0, 12.6 Hz), 3.24 (1H, dt, J=3.6, 12.6 Hz), 3.62 (1H, dd,J=3.6, 11.2 Hz), 4.04 (1H, d, J=2.4 Hz), 4.14 (1H, dt, J=3.0, 11.2 Hz),4.48 (1H, d, J=2.4 Hz), 4.90 (1H, q, J=6.8 Hz), 7.21-7.32 (7H, m), 7.64(1H, s). MS (CI⁺) m/z 420 (M⁺ +1, 20%), 178 (100%).

Analysis Calcd. for C₂₀ H₁₉ F₆ NO₂ : C, 57.28; H, 4.57; N, 3.34; F,27.18; Found: C, 57.41; H, 4.61; N, 3.29; F, 27.23%.

DESCRIPTION 202-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-chlorobut-2-yn-yl)-3-(S)-phenylmorpholine

The compound of Description 19 was reacted with 1,4-dichlorobut-2-ynefollowing the procedure illustrated in Description 6 to afford the titlecompound. ¹ H NMR (250 MHz, CDCl₃) δ1.48 (3H, d, J=6.5 Hz), 2.85-3.00(2H, m), 3.33 (2H, br s), 3.60 (1H, d, J=2.8 Hz), 3.72 (1H, br dt), 4.14(2H, t, J=1.75 Hz), 4.31-4.41 (2H, m), 4.87 (1H, q, J=6.5 Hz), 7.17 (2H,s), 7.30-7.35 (3H, m), 7.37 (2H, m), 7.61 (1H, s).

DESCRIPTION 214-Benzyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 4 (12.8 g) was dissolved in tetrahydrofuran(50 ml) and the mixture was cooled in ice. Borane (49 ml of 1.0M intetrahydrofuran) was added dropwise and the reaction mixture was stirredat room temperature for 3 hr. The solution was cooled in ice and sodiumhydroxide (120 ml, 1M) and hydrogen peroxide (36 ml, 30 wt. %) wereadded dropwise cautiously. The resulting mixture was stirred for 1 h,then diluted with water (200 ml) and extracted with ethyl acetate (3×50ml). The organic extracts were washed with sodium sulfite and thenbrine. The organic phase was dried (MgSO₄) and evaporated to give aclear oil. Plc (50:50 ethyl acetate/hexane) indicated two main productswhich were separated by flash chromatography on silica using a gradientelution of 1-30% ethyl acetate in hexane. The minor product eluted first(2.3 g) and the major product eluted last (8 g). The major product wasisolated as a white foam. ¹ H NMR (360 MHz, DMSO-d₆) δ2.23-2.29 (1H, m),2.73 (1H, d), 2.80 (1H, d, J=13.0 Hz), 3.48 (1H, d, J=3.5 Hz), 3.45-3.52(2H, m), 3.56-3.65 (2H, m), 4.00-4.06 (1H, m), 4.37 (1H, d, J=3.0 Hz),4.81 (1H, t, J=6.0 Hz), 4.92 (1H, t, J=5.5 Hz), 7.14 (2H, t, J=9.0 Hz),7.23-7.33 (5H, m), 7.35 (2H, s), 7.57 (2H, t), 7.85 (1H, s). MS (CI+)m/z 544 (M⁺ +1, 100%).

DESCRIPTION 222-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 21 (8 g) as dissolved in ethyl acetate (100ml) and isopropanol (50 ml) and palladium on charcoal (1.5 g) was addedto the solution. This mixture was hydrogenated at 40 psi overnight. Thecatalyst was removed by filtration and the solvents were removed invacuo. The residue was purified by flash silica chromatography using1-10% methanol in dichloromethane as eluant. This afforded the productas a white powder (5.7 g, 90%). ¹ H NMR (360 MHz, CDCl₃) δ2.68-2.73 (1H,m), 3.03-3.15 (1H, m), 3.43-3.65 (3H, m), 3.95 (1H, d, J=3.0 Hz), 4.1₂.422 (1H, m), 4.40 (1H, d, J=3.0 Hz), 4.89 (1H, t, J=7.0 Hz), 6.99 (t,J=9.0 Hz), 7.15 (2H, s), 7.26-7.31 (1H, m), 7.62 (1H, s). MS (CI+) m/z454 (M⁺ +1, 100%).

DESCRIPTION 233-(S)-(4-Fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Step A:4-Benzyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl1)-2-hydroxyethoxy)morpholine

The compound of Description 9 (0.8 g) was dissolved in tetrahydrofuran(5 ml) at room temperature and borane (5 ml, 1.0M in tetrahydrofuran)was added. The solution was stirred under nitrogen for 30 min until allstarting material had reacted. Hydrogen peroxide (5 ml, 29% aq.) andsodium hydroxide (10 ml, 4N) were added dropwise to the cooled (0° C.)solution with much effervescence. The resulting mixture was extractedwith ethyl acetate, the organic phase was washed with sodium bisulfiteand brine, dried (MgSO₄) and evaporated to afford a colourless oil (1g). This material was not purified further but reacted as described inthe following step.

Step B:3-(S)-(4-Fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

The compound of (a) above (1 g) was dissolved in ethylacetate/2-propanol (20 ml, 3:1) and treated with Pd on carbon (100 mg).The mixture was hydrogenated at 60 psi for 12 h. The catalyst wasremoved by filtration and the solvent was removed in vacuo. The residuewas purified by medium pressure chromatography on silica (Lobar) using5% methanol in dichloromethane as eluant. The product was recrystallisedfrom ether.

¹ H NMR (360 MHz, DMSO-d₆) δ2.77-3.04 (3H, m), 3.36-3.51 (2H, m), 3.93(1H, br s), 4.05-4.13 (1H, m), 4.36 (1H, d, J=2.0 Hz), 4.72 (1H, t,J=5.0 Hz), 4.98 (1H, t, J=7.0 Hz), 6.66 (1H, d, J=9.2 Hz), 6.89 (1H, s),7.10 (2H, t, J=9.0 Hz), 7.33-7.37 (2H, m), 7.41 (1H, d, J=9.0 Hz); MS(CI+) m/z 404 (M⁺ +1, 100).

DESCRIPTION 244-(4-(Chlorobut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

The compound of Description 23 was reacted with 1,4-dichlorobut-2-ynefollowing the procedure illustrated in Description 6 to afford the titlecompound. ¹ H NMR (250 MHz,CDCl₃) δ2.88-3.00 (3H, m), 3.31 (2H, m),3.64-3.76 (4H, m), 4.15 (1H, m), 4.32-4.43 (2H, m), 4.79 (1H, m), 6.43(1H, b d, J=9.1 Hz), 6.79 (1H, s), 7.03-7.13 (3H, m), 7.38 (2H, m), MS(ES³⁰ ) m/z=490.

DESCRIPTION 252-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-tert-butyldimethylsilyloxyethoxy)-3-(S)-(4-fluorophenyl)morpholine

The product from Description 22 (2 g) was dissolved in anhydrousdichloromethane (16 ml), under nitrogen, and cooled to 0° C.2,6-Lutidine (0.5 ml) and tert-butyldimethyltrifluoromethane sulfonate(1.0 ml) were then added and the mixture stirred for 15 mins. Thereaction mixture was washed (H20, brine), dried (MgSO₄) and evaporatedin vacuo. Purification by gravity silica column using 20%-50%ethylacetate/petrol as eluant afforded the title compound as acolourless oil. ¹ H NMR (250 MHz, CDCl₃) δ-0.04 (3H, s), 0.00 (3H, s),0.87 (9H, s), 3.15-3.36 (2H, m), 3.64-370 (2H, m), 3.90-3.96 (1H, m),4.10 (1H, d, J=2.2 Hz), 4.22-4.53 (1H, m), 4.53 (1H, d, J=2.2 Hz), 4.91(1H, t, J=5.9 Hz), 7.04-7.14 (2H, m), 7.29-7.36 (4H, m), 7.74 (1H, brs). MS (ES⁺) m/z=567.

DESCRIPTION 262-(R)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-tert-butyldimethylsilyloxyethoxy)-3-(S)-(4-fluorophenyl)-4-(4-chlorobut-2-ynyl)morpholine

The compound of Description 25 and 1,4-dichlorobut-2-yne was reactedfollowing the procedure illustrated in Description 6 to afford the titlecompound as a clear oil. ¹ H NMR (360 MHz, CDCl₃) δ0.00 (3H, s), 0.04(3H, s), 0.91 (9H, s), 2.95-3.09 (2H, m), 3.40 (2H, br s), 3.72-3.83(3H, m), 4.01 (1H, dd, J=10.2, 5.5 Hz), 4.25 (2H, m), 4.50 (2H, m), 4.9(1H, t, J=5.9 Hz), 7.15 (2H, t, J=8.7 Hz), 7.29 (2H, s), 7.52 (2H, brs), 7.76 (1H, s).

DESCRIPTION 274-Benzyl-2-(R)-(3-fluoro-5-(trifluoromethyl)benzoyloxy)-3-(S)-phenylmorpholine

The title compound was prepared in an analogous fashion to Description17 using the product from Description 16 and3-fluoro-5-(trifluoromethyl)benzoyl chloride. ¹ H NMR (250 MHz,CDCl₃)δ2.47 (1H, dt, J=3.4, 12.0 Hz), 2.93 (1H, s), 2.98 (1H, s), 3.72-3.80(2H, m), 3.98 (1H, d, J=13.5 Hz), 4.11-4.24 (1H, m), 7.22-7.36 (8H, m),7.56 (3H, m), 7.89 (1H, d, J=8.0 Hz), 8.10 (1H, s).

DESCRIPTION 284-Benzyl-2-(R)-(1-(3-fluoro-5-(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-phenylmorpholine

The title compound was prepared as a colourless oil in an analogousfashion to Description 18 using the product from Description 27. ¹ H NMR(250 MHz,CDCl₃) δ2.41 (1H, dt, J=3.6, 12.0 Hz), 2.87-2.94 (2H, m), 3.62(1H, m), 3.72 (1H, d, J=2.8 Hz), 3.97-4.17 (2H, m), 7.23-7.43 (10 H, m),7.54 (1H, s), 7.63 (2H, m).

DESCRIPTION 292-(R)-(1-(R)-(3-Fluoro-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine

The title compound was prepared in an analogous fashion to Description19 using the product from Description 28. ¹ H NMR (250 MHz,CDCl₃) δ1.33(3H, d, J=6.6 Hz), 1.93 (1H, br s), 3.02-3.22 (2H, m), 3.53 (1H, m),3.96 (1H, d, J=2.4 Hz), 4.00-4.11 (1H, m), 4.38 (1H, d, J=2.4 Hz), 4.75(1H, m), 6.24 (1H, d, J=9.2 Hz), 6.80 (1H, s), 6.98 (1H, d, J=8.3 Hz),7.13-7.31 (5H, m). MS (ES⁺) m/z 369.

DESCRIPTION 304-(4-Chlorobut-2-yn-yl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine

The title compound was prepared in an analogous fashion to Description20 using the product from Description 29. ¹ H NMR (250 MHz,CDCl₃) δ1.43(3H, d, J=6.6 Hz), 2.86-2.99 (2H, m), 3.37 (2H, s), 3.61 (1H, d, J=2.6Hz), 3.68-3.73 (1H, m), 4.08-4.18 (2H, m), 4.30-4.41 (2H, m), 4.74-4.82(1H, m), 6.26 (1H, d, J=9.09 Hz), 6.84 (1H, s), 7.02 (2H, d, J=8.4 Hz),7.35 (5H, br s).

EXAMPLE 12-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine

The compound of Description 6 (0.5 g), potassium carbonate (0.4 g) andmorpholine (0.1 g) were stirred in dry dimethylformamide under nitrogenfor 5 h. The mixture was partitioned between ethyl acetate and water,the organic phase was washed with brine, dried (MgSO₄) and evaporated invacuo. The residue was purified on silica using ethyl acetate in petrol(1:1) followed by ethyl acetate (100%) as eluent. This afforded thetitle compound as a clear oil. ¹ H NMR (250 MHz, CDCl₃) δ1.48 (3H, d,J=6.6 Hz), 2.52 (4H, m), 2.83-3.01 (2H, m), 3.29 (4H, s), 3.59 (1H, d,J=2.77 Hz), 3.69-3.75 (5H, m), 4.29-4.39 (2H, m), 4.88 (1H, q, J=6.5Hz), 7.0 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.36 (2H, br s), 7.63 (1H, s).

M/S (ES⁺) m/z 575 (MH⁺, 100%).

EXAMPLE 22-R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine

This compound was prepared from the reaction of the compound ofDescription-6 and dimethylamine according to the procedure described inExample 1. ¹ H NMR (250 MHz, CDCl₃) δ1.48 (3H, d, J=6.6 Hz), 2.27 (6H,s), 2.84 (1H, br d), 2.98 (1H, dd, J=3.6, 11.8 Hz), 3.29 (4H, m), 3.63(1H, d, J=2.8 Hz), 3.71 (1H, m), 4.34 (2H, m), 4.88 (1H, q, J=6.6 Hz),7.02 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.37 (2H, br s), 7.63 (1H, s). MS(ES⁺) m/z 533 (MH⁺, 100%).

EXAMPLE 34-(4-Azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine

This compound was prepared from the reaction of the compound ofDescription 6 and azetidine according to the procedure described inExample 1. ¹ H NMR (250 MHz, CDCl₃) δ1.47 (3H, d, J=6.6 Hz), 1.99-2.10(2H, m), 2.82-2.86 (1H, m), 2.99 (1H, dd, J=3.7, 11.9 Hz), 3.21-3.32(8H, m), 3.64 (1H, d, J=2.79 Hz), 3.71 (1H, m), 4.29-4.40 (2H, m), 4.88(1H, q, J=6.6 Hz), 7.02 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.38 (2H, brs). 7.63 (1H, s).

EXAMPLE 42-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S-(4-fluorophenyl)-4-(4-(imidazolyl)but-2-yn-yl)morpholine

The compound of Description 6 was added to a solution of imidazole (77mg) and sodium hydride (42 mg, 60% in oil) in dry dimethylformamide. Themixture was allowed to stir for 16 h and then was partitioned betweenwater and ethyl acetate. The organic layer was washed with water, brineand dried (MgSO₄) and evaporated in vacuo. The compound was purified onsilica using dichloromethane (100%) as eluent and gradient elution todichloromethane/methanol/ammonia (97:2:1). This afforded the titlecompound as a colourless oil. ¹ H NMR (250 MHz, CDCl₃) δ1.48 (3H, d,J=6.6 Hz), 2.86-2.91 (3H, m), 3.30 (2H, s), 3.51 (1H, d, J=2.8 Hz),3.68-3.74 (1H, m), 4.28-4.39 (2H, m), 4.87 (1H, q, J=6.5 Hz), 6.99-7.09(4H, m), 7.16 (2H, s), 7.27 (1H, br s), 7.57 (1H, s), 7.63 (1H, s). MS(ES⁺) m/z 556 (MH⁺, 100%).

EXAMPLE 52-(R)-(-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine

This compound was prepared from the reaction of the compound ofDescription 6 and N-methylpiperazine according to the proceduredescribed in Example 1. ¹ H NMR (250 MHz, CDCl₃) δ1.47 (3H, d, J=6.6Hz), 1.9-1.95 (2H, m), 2.30 (3H, s), 2.4-2.6 (6H, m), 2.83-2.86 (1H, m),2.93 (1H, dt, J=12.0, 3.6 Hz), 3.21-3.29 (4H, m), 3.59 (1H, d, J=3.0Hz), 3.70 (1H, d, J=12.0 Hz), 4.33 (2H, q, J=12.6 Hz), 4.87 (1H, q,J=6.6 Hz), 7.00 (2H, t, J=7.2 Hz), 7.17 (2H, s), 7.36 (2H, br m), 7.62(1H, s).

EXAMPLE 64-(4-Bis(methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluorometbyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 6 was reacted with bis(methoxyethyl)amineaccording to the procedure described in Example 1 to afford the titlecompound as a clear oil. ¹ H NMR (360 MHz, CDCl₃) δ1.48 (3H, d, J=6.8Hz), 2.74 (4H, br m), 2.84 (1H, br d, J=12 Hz), 2.95 (1H, dt, J=12.3Hz), 3.29 (2H, br s), 3.33 (6H, s), 3.49 (6H, m), 3.61 (1H, d, J=3 Hz),3.70 (1H, br d), 4.33 (2H, app. q), 4.87 (1H, q, J=6.8 Hz), 7.01 (2H, t,J=8.5 Hz), 7.17 (2H, s), 7.36 (2H, m), 7.63 (1H, s). MS (ES) m/z 621 (M⁺+, 100%).

EXAMPLE 72-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine

The compound of Description 7 (0.85 g), paraformaldehyde (66 mg),pyrrolidine (0.18 ml) and copper (I)chloride (8 mg) in dioxane wereheated at 80° C. for 4 h (J. Med. Chem. 1985, 28, 1760). The mixture wascooled and concentrated in vacuo. The residue was purified bychromatography on silica using ethyl acetate in hexane (1:4→100%)followed by 10% methanol in ethyl acetate as eluant. This afforded theproduct as a viscous oil (870 mg, 87%). ¹ H NMR (360 MHz, CDCl₃) δ1.47(3H, d, J=6.6 Hz), 1.80 (4H, m), 2.59 (4H, br s), 2.83 (1H, d, J=11.1Hz), 2.95 (1H, ddd, J=3.6, 11.9, 11.9 Hz), 3.28 (2H, s), 3.41 (2H, s),3.61 (1H, d, J=2.7 Hz), 3.71 (1H, dd, J=2.2, 11.1Hz), 4.32 (2H, m), 4.87(1H, q, J=6.6 Hz), 7.01 (2H, t, J=8.6 Hz), 7.17 (2H, s), 7.36 (2H, brs), 7.63 (1H, s). IR (film) ν-2810 (m), 1741 (w), 1608 (m), 1510 (s),1280 (s), 1060 (s), 900 (s), 685 (s) cm⁻¹ MS (CI+) m/z 559 (ME, 100%).

EXAMPLE 83-(S)-(4-Fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-morpholinobut-2-ynyl)morpholine

The compound of Description 11 was reacted with morpholine according tothe procedure described in Example 1. ¹ H NMR (360 MHz, CDCl₃) δ1.43(3H, d, J=6.6 Hz), 2.53 (4H, t, J=4.4 Hz), 2.85 (1H, br d, J=10.5 Hz),2.94 (1H, dt, J=11.7, 3.5 Hz), 3.31 (4H, d, J=5.5 Hz), 3.60 (1H, d,J=2.8 Hz), 3.66-3.76 (5H, m), 4.33 (2H, dt, J=13.3, 2.8 Hz), 4.77 (1H,q, J=6.6 Hz), 6.37 (1H, d, J=9.1 Hz), 6.81 (1H, s), 7.00-7.07 (3H, m),7.35 (2H, br s). MS (CI+) m/z 525 (M+1, 98%), 524 (M+, 100).

EXAMPLE 93-(S)-(4-Fluorophenyl)-4-(4-morpholinobut-2-ynyl)-2-(R)-(1-(3-(trifluoromethyl)phenyl)ethoxy)morpholine

The compound of Description 15 was reacted with morpholine according tothe procedure described in Example 1. ¹ H NMR (360 MHz, CDCl₃) δ1.44(3H, d, J=6.6 Hz), 2.52 (4H, t, J=4.6 Hz), 2.84 (1H, br d, J=11.6 Hz),2.94 (1H, dt, J=11.9, 3.5 Hz), 3.30 (4H, dd, J=3.6, 1.4 Hz), 3.58 (1H,d, J=2.8 Hz), 3.66-3.75 (5H, m), 4.35 (1H, dt, J=11.7, 2.9 Hz), 4.78(1H, q, J=6.6 Hz), 6.80 (1H, d, J=7.7 Hz), 6.96-7.04 (3H, m), 7.15 (1H,t, J=7.7 Hz), 7.35 (3H, br d, J=7.5 Hz). MS (CI+) m/z 507 (M+1, 100%).

EXAMPLE 104-(4-Azetidinylbut-2-ynyl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(3-(trifluoromethyl)phenyl)ethoxy)morpholine

The compound of Description 15 was reacted with azetidine according tothe procedure described in Example 1. ¹ H NMR (360 MHz, CDCl₃) δ1.44(3H, d, J=6.6 Hz), 2.04 (2H, quin, J=7.1 Hz), 2.84 (1H, br d, J=11.8Hz), 2.98 (1H, dt, J=11.9, 3.6 Hz), 3.02-3.32 (8H, m), 3.62 (1H, d,J=2.8 Hz), 3.69 (1H, m), 4.33 (1H, d, J=2.8 Hz), 4.36 (1H, dt, J=11.8,2.7 Hz), 4.79 (1H, q, J=6.5 Hz), 6.80 (1H, d, J=7.6 Hz), 6.96-7.04 (3H,m) 7.15 (1H, t, J=7.7 Hz), 7.35 (3H, br d, J=7.7 Hz). MS (CI+) m/z 477(M+1, 100%).

EXAMPLE 112-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methylamino)but-2-yn-yl)-3-(S)-phenylmorpholine

The compound of Description 20 was reacted withN-(2-methoxyethyl)-N-methylamine according to the procedure described inExample 1 to afford the title compound. ¹ H NMR (250 MHz, CDCl₃) δ1.48(3H, d, J=6.5 Hz), 2.33 (3H, s), 2.62 (2H, t, J=5.5 Hz), 2.84 (1H, brd), 2.98 (1H, dt, J=3.5, 12.0 Hz), 3.33-3.34 (2H, m), 3.35 (3H, s), 3.41(2H br s), 3.46 (2H, t, J=5.5 Hz), 3.63 (1H, d, J=2.8 Hz), 3.72 (1H, brd), 4.3₁.4.41 (2H, m), 4.86 (1H, q, J=6.5 Hz), 7.16 (2H, s), 7.31-7.36(3H, m), 7.36 (2H, m), 7.60 (1H, s).

EXAMPLE 122-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine

The compound of Description 20 was reacted withN-cyclopropyl-N-(2-methoxyethyl)amine according to the proceduredescribed in Example 1 to afford the title compound. ¹ H NMR (360 MHz,CDCl₃) δ0.47-0.49 (4H, m), 1.48 (3H, d, J=6.5 Hz), 1.94 (1H, br quin),2.85-2.88 (3H, m), 2.98 (1H, dt, J=3.6, 12.0 Hz), 3.33 (3H, s),3.33-3.35 (2H, m), 3.47-3.52 (4H, m), 3.63 (1H, d, J=2.8 Hz), 3.71 (1H,dd, J=2.0, 11.0 Hz), 4.32-4.40 (2H, m), 4.86 (1H, q, J=6.5 Hz), 7.16(2H, s), 7.30-7.31 (3H, m), 7.37 (2H, m), 7.60 (1H, s).

EXAMPLE 132-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl)-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine

The compound of Description 20 was reacted withN-isopropyl-N-(2-methoxyethyl)amine according to the procedure describedin Example 1 to afford the title compound. ¹ H NMR (360 MHz, CDCl₃)δ1.06 (6H, d, J=6.0 Hz), 1.47 (3H, d, J=6.5 Hz), 2.72 (2H, t, J=6.0 Hz),2.82-3.00 (3H, m), 3.30-3.33 (2H, m), 3.33 (3H, s), 3.41-3.47 (4H, m),3.61 (1H, d, J=2.5 Hz), 3.71 (1H, br d), 4.32-4.39 (2H, m), 4.86 (1H, q,J=6.5 Hz), 7.16 (2H, s), 7.27-7.31 (3H, m), 7.36 (2H, br s), 7.60 (1H,s).

EXAMPLE 144-(4-(N,N-Dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine

The compound of Description 24 was reacted with dimethylamine accordingto the procedure described in Example 1 to afford the title compound asa clear oil. ¹ H NMR (360 MHz,CDCl₃) δ2.28 (6H, s), 2.88-2.97 (2H, m),3.24 (2H, s), 3.30 (2H, d, J=9.9 Hz), 3.62 (3H, m), 3.72 (1H, m),4.35-4.23 (2H, m), 4.79 (1H, m), 6.42 (1H, d, J=8.6 Hz), 6.79 (1H, s),7.04-7.12 (3H, m), 7.38 (2H, vbr s). M/Z (ES⁺) m/z=498.

EXAMPLE 154-(4-Azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

The title compound was prepared from the reaction of the compound ofDescription 24 and azetidine according to the procedure described inExample 1. ¹ H NMR (360 MHz,CDCl₃) δ2.04 (2H, m), 2.40 (1H, vb s),2.88-2.97 (3H, m), 3.21-3.36 (7H,m), 3.57-3.74 (4H, m), 4.35-4.42 (2H,m), 4.77-4.81 (1H, m), 6.42 (1H, d, J=8.8 Hz), 6.77 (1H, s), 7.04-7.12(3H, m), 7.38 (2H, vbr s).

EXAMPLE 162-(R)-(I-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine

The title compound was prepared from the reaction of the compound ofDescription 26 and dimethylamine according to the procedure described inExample 1. Deprotection was effected by stirring with tetrabutylammoniumfluoride (1.0M) in tetrahydrofuran for 60 minutes. The mixture waspartitioned between ammonium chloride solution and ethyl acetate, andthe organic layer washed (H₂ O, brine), dried (MgSO₄) and evaporated invacuo. The residue was purified on a gravity silica column using 5-10%methanol/ethyl acetate as eluant giving the title compound as an oil. ¹H NMR (360 MHz,CDCl₃) δ2.28 (6H, s), 2.88-2.98 (2H, m), 3.21-3.34 (4H,m), 3.64-3.75 (4H, m), 4.36-4.42 (2H, m), 4.86-4.90 (1H, m), 7.05 (2H,t, J=8.7 Hz), 7.17 (2H, s), 7.39 (2H, vbr s), 7.67 (1H, s). MS (ES⁺) 549(M+H)⁺.

EXAMPLE 174-(4-Azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine

The title compound was prepared from the reaction of the compound ofDescription 26 and azetidine according to the procedure described inExample 16, which gave a white foam. ¹ H NMR (250 MHz,CDCl₃) δ2.05 (2H,m), 2.37 (1H, vbr s), 2.92 (2H, m), 3.18-3.29 (8H, m), 3.66-3.76 (4H,m), 4.35-4.47 (2H, m), 4.87-4.91 (1H, m), 7.06 (2H, t, J=8.7 Hz), 7.17(2H, s), 7.41 (2H, br s), 7.67 (1H, s). M/S (ES⁺) m/z 560.

EXAMPLE 184-(4-N-Bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 6 was reacted with methylaminoacetaldehydedimethyl acetal according to the procedure described in Example 1 toafford the title compound. ¹ H NMR (250 MHz,CDCl₃) δ1.48 (3H, d, J=6.6Hz), 2.36 (3H, s), 2.58 (2H, d, J=5.4 Hz), 2.81-3.03 (2H, m), 3.30 (2H,m), 3.36 (6H, s), 3.43 (2H, br s), 3.61 (1H, d, J=2.8 Hz), 3.68-3.74(1H, m), 4.29-4.40 (2H, m), 4.49 (1H, t, J=5.4 Hz), 4.88 (1H, m), 7.02(2H, t, J=8.7 Hz), 7.17 (2H, s), 7.37 (2H, vbr s), 7.63 (1H, s).

EXAMPLE 192-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine

The compound of Description 6 was reacted with(S)(+)-2-(methoxymethyl)pyrrolidine according to the procedure describedin Example 1 to afford the title compound. ¹ H NMR (250 MHz,CDCl₃) δ1.48(2H, d, J=6.6 Hz), 1.70-2.05 (4H, m), 2.83-2.97 (3H, m), 3.32 (4H, brs), 3.38 (3H, s), 3.45 (1H, m), 3.58 (1H, m), 3.70-3.83 (4H, m),4.29-4.39 (3H, m), 4.87 (1H, m), 7.02 (2H, t, J=8.7 Hz), 7.16 (2H, s),7.36 (2H, vbr s), 7.63 (1H, s).

EXAMPLE 20 4-(4-(7-Azabicyclo2.2.1!heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 6 was reacted with 7-azabicyclo2.2.1!heptane hydrochloride according to the procedure described inExample 1 to afford the title compound. ¹ H NMR (250 MHz,CDCl₃) δ1.30(4H, m), 1.48 (3H, d, J=6.6 Hz), 1.75 (4H, m), 2.83-3.03 (2H, m), 3.17(2H, d, J=1.8 Hz), 3.27 (2H, d, J=1.3 Hz), 3.37 (2H, m), 3.62 (1H, d,J=2.8 Hz), 3.68-3.73 (1H, m), 4.28-4.39 (2H, m), 4.88 (1H, q, J=6.6 Hz),7.01 (2H, t, 8.7 Hz), 7.17 (2H, s), 7.37 (2H, br s), 7.63 (1H, s).

EXAMPLE 212-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine

The compound of Description 6 was reacted with N,N-diisopropylamineaccording to the procedure described in Example 1 to afford the titlecompound. ¹ H NMR (360 MHz,CDCl₃) δ1.08 (12H, d, J=4.6 Hz), 1.47 (3H, d,J=4.6 Hz), 2.81 (1H, br d, J=7.5 Hz), 2.97 (1H, dt, J=2.6 Hz, 8.3 Hz),3.16 (2H, m), 3.25 (2H, t, J=1.3 Hz), 3.41 (2H, t, J=1.3 Hz), 3.61 (1H,d, J=2.0 Hz), 3.70 (1H, m), 4.27-4.37 (2H, m), 4.87 (1H, q, J=4.6 Hz),7.01 (2H, t, J=6.0 Hz), 7.17 (2H, s), 7.35 (2H, br s), 7.63 (1H, s).

EXAMPLE 222-(R)-(1-(R)-(3-Fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine

The title compound was prepared from the reaction of the compound ofDescription 30 and 2-(S)-(methoxymethyl)pyrrolidine according to theprocedure described in Example 1. ¹ H NMR (250 MHz,CDCl₃) δ1.43 (3H, d,J=6.6 Hz), 1.90 (4H, m), 2.62 (1H, q, J=7.54 Hz), 2.78-2.86 (2H, m),2.93-3.03 (2H, m), 3.27-3.41 (7H, m), 3.58 (2H, m), 3.64 (1H, d, J=2.84Hz), 3.71 (1H, dd, J₁ =1.8 Hz, J₂ =2.18 Hz), 4.36 (1H, td, J₁ =11.02 Hz,J₂ =2.83 Hz), 4.78 (1H, q, J=6.57 Hz), 6.25 (1H, d, J=9.12 Hz), 6.84(1H, s), 7.02 (1H, d, J=8.30 Hz), 7.34 (5H, s).

EXAMPLE 232-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2-(2-(S)-hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine

The title compound was prepared from the reaction of the compound ofDescription 6 and 2-(S)-(hydroxymethyl)pyrrolidine according to theprocedure described in Example 1. ¹ H NMR (250 MHz,CDCl₃) δ1.48 (3H, d,J=6.60 Hz), 1.71-1.90 (4H, m), 2.18 (2H, br s), 2.61-3.06 (5H, m), 3.29(2H, s), 3.58 (2H, m), 3.64 (1H, d, J=2.83 Hz), 3.77 (1H, dd, J₁ =11.18Hz, J₂ =2.18 Hz), 4.34 (2H, td, J₁ =11.02 Hz, J₂ =2.83 Hz), 4.88 (1H, q,J=6.60 Hz), 7.02 (2H, t, J=8.65 Hz), 7.27 (2H, s), 7.36 (2H, br s), 7.63(1H, s). MS m/z (ES+) 589.

The following examples illustrate pharmaceutical compositions accordingto the invention.

    ______________________________________                                        EXAMPLE 24A Tablets containing 1-25 mg of compound                                          Amount mg                                                       ______________________________________                                        Compound of formula (I)                                                                       1.0        2.0    25.0                                        Microcrystalline cellulose                                                                    20.0       20.0   20.0                                        Modified food corn starch                                                                     20.0       20.0   20.0                                        Lactose         58.5       57.5   34.5                                        Magnesium stearate                                                                            0.5        0.5    0.5                                         ______________________________________                                    

    ______________________________________                                        EXAMPLE 24B Tablets containing 26-100 mg of compound                                        Amount mg                                                       ______________________________________                                        Compound of formula (I)                                                                       26.0       50.0   100.0                                       Microcrystalline cellulose                                                                    80.0       80.0   80.0                                        Modified food corn starch                                                                     80.0       80.0   80.0                                        Lactose         213.5      189.5  139.5                                       Magnesium stearate                                                                            0.5        0.5    0.5                                         ______________________________________                                    

The compound of formula (I), cellulose, lactose and a poriton of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

    ______________________________________                                        EXAMPLE 25 Parenteral injection                                                                    Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1 to 100 mg                                            Citric acid monohydrate                                                                              0.75 mg                                                Sodium phosphate       4.5 mg                                                 Sodium chloride        9 mg                                                   Water for injection    to 10 ml                                               ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The compound of formula (I) isdissolved or suspended in the solution and made up to volume.

    ______________________________________                                        EXAMPLE 26 Topical formulation                                                                     Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1-10 g                                                 Emulsifying wax        30 g                                                   Liquid paraffin        20 g                                                   White soft paraffin    to 100 g                                               ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. Thecompound of formula (I) is added and stirring continued until dispersed.The mixture is then cooled until solid.

EXAMPLE 27A

(Surface-Active Agent) Injection Formulation

Compound of formula (I) up to 10 mg/kg

Tween 80™ up to 2.5%

in 5% aqueous mannitol (isotonic)!

The compound of formula (I) is dissolved directly in a solution of thecommercially available Tween 80™, (polyoxyethylenesorbitan monooleate)and 5% aqueous mannitol (isotonic).

EXAMPLE 27B

(Emulsion) Injection Formulation

Compound of formula (I) up to 30 mg/ml

Intralipid™ (10-20%)

The compound of formula (I) is dissolved directly in the commerciallyavailable Intralipid™ (10 or 20%) to form an emulsion.

    ______________________________________                                        Example 27C - Alternative (Emulsion) Injectable Formulation                                        Amount                                                   ______________________________________                                        Compound of formula (I)                                                                              0.1-10 mg                                              Soybean oil            100 mg                                                 Egg phospholipid       6 mg                                                   Glycerol               22 mg                                                  Water for injection    to 1 ml                                                ______________________________________                                    

All materials are sterilized and pyrogen free. The compound of formula(I) is dissolved in soybean oil. An emulsion is then formed by mixingthis solution with the egg phospholipid, glycerol and water. Theemulsion is then sealed in sterile vials.

We claim:
 1. A compound of the formula (I): ##STR12## wherein X is agroup of the formula NR⁶ R⁷ or a C-- or N-linked imidazolyl ring;Y ishydrogen or C₁₋₄ alkyl optionally substituted by a hydroxy group; R¹ ishydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CN, SR^(a),SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, wherein R^(a) andR^(b) each independently represent hydrogen or C₁₋₄ alkyl; R² ishydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄ alkoxy orCF₃ ; R³ is hydrogen, halogen or CF₃ ; R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, hydroxy, CF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a),CO₂ R^(a), CONR_(a) R^(b), C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₄ alkylsubstituted by C₁₋₄ alkoxy, wherein R^(a) and R^(b) are as previouslydefined; R⁵ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted byC₁₋₄ alkoxy or CF₃ ; R⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, phenyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxyor hydroxy; R⁷ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, phenyl, or C₂₋₄ alkyl substituted by one or twosubstituents selected from C₁₋₄ alkoxy, hydroxy or a 4, 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S; or R⁶ and R⁷, together with the nitrogen atom to which they areattached, form a saturated or partially saturated heterocyclic ring of 4to 7 ring atoms, which ring may optionally contain in the ring oneoxygen or sulphur atom or a group selected from NR⁸, S(O) or S(O)₂ andwhich ring may be optionally substituted by one or two groups selectedfrom hydroxyC₁₋₄ alkyl, C₁₋₄ alkoxyC₁₋₄ alkyl, oxo, COR^(a) or C₂ R^(a)where R^(a) is as previously defined; or R⁶ and R⁷ together with thenitrogen atom to which they are attached, form a non-aromaticazabicyclic ring system of 6 to 12 ring atoms; R⁸ is hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄ alkyl or C₁₋₄ alkoxyC₁₋₄ alkyl; and R^(9a) and R^(9b)are each independently hydrogen or C₁₋₄ alkyl, or R^(9a) and R^(9b) arejoined so, together with the carbon atoms to which they are attached,there is formed a C₅₋₇ ring;or a pharmaceutically acceptable saltthereof.
 2. A compound as claimed in claim 1 whereinX is a group of theformula NR⁶ R⁷ or a C-- or N-linked imidazolyl ring; Y is hydrogen orC₁₋₄ alkyl optionally substituted by a hydroxy group; R¹ is hydrogen,halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₄alkyl substituted by C₁₋₄ alkoxy, wherein R^(a) and R^(b) eachindependently represent hydrogen or C₁₋₄ alkyl; R² is hydrogen, halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄ alkoxy or CF₃ ; R³ ishydrogen, halogen or CF₃ ; R⁴ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, CF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a)R^(b), C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄alkoxy, wherein R^(a) and R^(b) are as previously defined; R⁵ ishydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄ alkoxy orCF₃ ; R⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, phenyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy or hydroxy; R⁷is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl,phenyl, or C₂₋₄ alkyl substituted by one or two substituents selectedfrom C₁₋₄ alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ringcontaining one or two heteroatoms selected from N, O and S; or R⁶ andR⁷, together with the nitrogen atom to which they are attached, form asaturated or partially saturated heterocyclic ring of 4 to 7 ring atoms,which ring may optionally contain in the ring one oxygen or sulphur atomor a group selected from NR⁸, S(O) or S(O)₂ and which ring may beoptionally substituted by one or two groups selected from hydroxyC₁₋₄alkyl, C₁₋₄ alkoxyC₁₋₄ alkyl, oxo, COR^(a) or CO₂ R^(a) where R^(a) isas previously defined; or R⁶ and R⁷ together with the nitrogen atom towhich they are attached, form a non-aromatic azabicyclic ring system of6 to 12 ring atoms; R⁸ is hydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl orC₁₋₄ alkoxyC₁₋₄ alkyl; and R^(9a) and R^(9b) are each independentlyhydrogen or C₁₋₄ alkyl, or R^(9a) and R^(9b) are joined so, togetherwith the carbon atoms to which they are attached, there is formed a C₅₋₇ring;or a pharmaceutically acceptable salt thereof.
 3. A compound asclaimed in claim 1 whereinX is a group of the formula NR⁶ R⁷ or a C-- orN-linked imidazolyl ring; Y is hydrogen or C₁₋₄ alkyl optionallysubstituted by a hydroxy group; R¹ is hydrogen, halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, CF₃, NO₂, CN, CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, wherein R^(a) andR^(b) each independently represent hydrogen or C₁₋₄ alkyl; R² ishydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄ alkoxy orCF₃ ; R³ is hydrogen, halogen or CF₃ ; R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CN, CO₂ R^(a), C₂₋₆ alkenyl, C₂₋₆ alkynylor C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, wherein R^(a) and R^(b) are aspreviously defined; R⁵ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxysubstituted by C₁₋₄ alkoxy or CF₃ ; R⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₄ alkyl, phenyl, or C₂₋₄ alkyl substitutedby C₁₋₄ alkoxy or hydroxy; R⁷ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkylC₁₋₄ alkyl, phenyl, or C₂₋₄ alkyl substituted by C₁₋₄alkoxy or hydroxy; or R⁶ and R⁷, together with the nitrogen atom towhich they are attached, form a saturated or partially saturatedheterocyclic ring of 4 to 7 ring atoms, and which ring may optionallycontain in the ring one oxygen or sulphur atom or a group selected fromNR⁸, S(O) or S(O)₂ and which ring may be optionally substituted by oneor two groups selected from hydroxyC₁₋₄ alkyl, C₁₋₄ alkoxyC₁₋₄ alkyl,oxo, COR^(a) or CO₂ R^(a) where R^(a) is as previously defined; R⁸ ishydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl or C₁₋₄ alkoxyC₁₋₄ alkyl; andR^(9a) and R^(9b) are each independently hydrogen or C₁₋₄ alkyl, orR^(9a) and R^(9b) are joined so, together with the carbon atoms to whichthey are attached, there is formed a C₅₋₇ ring;or a pharmaceuticallyacceptable salt thereof.
 4. A compound as claimed in claim 1 of formula(Ia): ##STR13## wherein A¹ is fluorine or CF₃ ;A² is fluorine or CF₃ ;A³ is fluorine or hydrogen; and X and Y are as defined in relation toformula (I);or a pharmaceutically acceptable salt thereof.
 5. A compoundas claimed in claim 1 formula (Ib): ##STR14## wherein R¹, R², R³, R⁴,R⁵, R^(9a), R^(9b), X and Y are as defined in claim 1; or apharmaceutically acceptable salt thereof.
 6. A compound as claimed inclaim 1 wherein X represents the NR⁶ R⁷ group where R⁶ and R⁷ eachindependently represent hydrogen, C₁₋₆ alkyl or C₂₋₄ alkyl substitutedby C₁₋₆ alkoxy, or R⁶ and R⁷, together with the nitrogen atom to whichthey are attached, form a saturated heterocyclic ring of 4, 5 or 6 atomswhich may optionally contain in the ring one oxygen atom or the groupNR⁸, where R⁸ is hydrogen or methyl.
 7. A compound as claimed in claim 6wherein, the group NR⁶ R⁷ represents NH₂, NHCH₃, N(CH₃)₂, azetidinyl,morpholino, thiomorpholino, piperazino, piperidino or pyrrolidino.
 8. Acompound as claimed in claim 1 wherein Y represents a methyl or CH₂ OHgroup.
 9. A compound selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-imidazolylbut-2-yn-yl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine;4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine;3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine;4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine;4-(4-(7-azabicyclo2.2.1!heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;2-(R)-(1-(R)-3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine;ora pharmaceutically acceptable salt thereof.
 10. Thecompound:2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;ora physiologically acceptable salt thereof.
 11. Thecompound:4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;ora physiologically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising a compound as claimed in claim 1 in associationwith a pharmaceutically acceptable carrier or excipient.
 13. A methodfor the treatment or prevention of physiological disorders associatedwith an excess of tachykinins, which method comprises administration toa patient in need thereof of a tachykinin reducing amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 14.A method according to claim 13 for the treatment or prevention of painor inflammation.
 15. A method according to claim 13 for the treatment orprevention of migraine.
 16. A method according to claim 13 for thetreatment or prevention of emesis.
 17. A process for the preparation ofa compound of claim 1, which comprises:(A) reacting a compound offormula (II): ##STR15## wherein R¹, R², R³, R⁴, R⁵, R^(9a), R^(9b) and Yare as defined in claim 1 with formaldehyde followed by the desiredamine of formula HNR⁶ R⁷, in the presence of a suitable catalyst; or (B)reacting a compound of formula (III): ##STR16## wherein R¹, R², R³, R⁴,R⁵, R^(9a), R^(9b) and Y are as defined in claim 1 and Hal is a halogenatom, by reaction with an amine of formula HNR⁶ R⁷ or imidazole, in thepresence of a base; or (C) the interconversion of a compound of formula(IV): ##STR17## using alkyl halides of the formula R⁶ -Hal and R⁷ -Hal,or a suitable dihalide designed to form a saturated heterocyclic ring,wherein R⁶ and R⁷ are as defined in claim 1, and Hal represents ahalogen atom, in the presence of a base; each process being followed,where necessary, by the removal of any protecting group where present;and when the compound of formula (I) is obtained as a mixture ofenantiomers or diastereoisomers, optionally resolving the mixture toobtain the desired enantiomer; and/or, if desired, converting theresulting compound of formula (I) or a salt thereof, into apharmaceutically acceptable salt thereof.